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Microbiology and Molecular Biology Reviews, June 1999, p. 308-333, Vol. 63, No. 2
Department of Medical Microbiology and
Immunology, Aarhus University, Aarhus, Denmark
1092-2172/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Mechanisms of T-Cell Activation by Human T-Cell
Lymphotropic Virus Type I
SUMMARY
INTRODUCTION
INFECTION OF T CELLS BY HTLV-I
ACTIVATION OF HTLV-I-INFECTED T CELLS
T-Cell Receptor-Mediated Activation
PKA signaling pathway.
PKC signaling pathway.
Ca2+ signaling pathway.
MAP kinase pathways.
Costimulatory Signaling Pathways
CD28 costimulation.
CD2 costimulation.
OX40 costimulation.
IL-2R Signaling Pathway
HTLV-I-Induced Cell Cycling
PROGRAMMED CELL DEATH IN HTLV-I-INFECTED T CELLS
IMMORTALIZATION AND TRANSFORMATION OF T CELLS BY HTLV-I
ACTIVATION OF THE CELLULAR IMMUNE SYSTEM BY HTLV-I-INFECTED
T CELLS
Activation of Non-Virus-Specific T Cells
Activation of Virus-Specific CD8+ T Cells
Structural Analysis of CD8+-T-Cell
Recognition of a Viral Peptide
Activation of Virus-Specific CD4+ T Cells
CONCLUSIONS
ACKNOWLEDGMENTS
REFERENCES
SUMMARY
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The interactions between human T-cell lymphotropic virus type I (HTLV-I) and the cellular immune system can be divided into viral interference with functions of the infected host T cell and the subsequent interactions between the infected T cell and the cellular immune system. HTLV-I-mediated activation of the infected host T cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction pathways, cell cycle control, and apoptosis. These properties of Tax may well explain the ability of HTLV-I to immortalize T cells. It is not clear, though, how HTLV-I induces T-cell transformation (interleukin-2 [IL-2] independence). Recent evidence suggests that Tax may promote the G1- to S-phase transition, although this may involve additional proteins. A role for other viral proteins that may constitutively activate the IL-2 receptor pathway has also been suggested. By virtue of their activated state, HTLV-I-infected T cells can nonspecifically activate resting, uninfected T cells via virus-mediated upregulation of adhesion molecules. This may favor viral dissemination. Moreover, the induction of a remarkably high frequency of antiviral CD8+ T cells does not appear to eliminate the infection. Indeed, individuals with a high frequency of virus-specific CD8+ T cells have a high viral load, indicating a state of chronic immune system stimulation. Thus, while an activated immune system is needed to eradicate the infection, the spread of the HTLV-I is also accelerated under these conditions. A detailed knowledge of the molecular interactions between virus-specific CD8+ T cells and immunodominant viral epitopes holds promise for the development of specific antiviral therapy.
INTRODUCTION
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The cellular immune response constitutes the specific host defense toward an established viral infection. Unlike the humoral immune response, which may neutralize and prevent the infection, the cellular immune response attempts to eliminate virus-infected cells. Typically, this is executed by cytotoxic CD8+ T lymphocytes (CTLs) that recognize viral peptides on the surface of the infected cells in the context of major histocompatibility complex (MHC) class I antigens. An unusual virus-host relationship occurs, however, when the virus persistently infects cells regulating the immune response, as exemplified by certain human herpesviruses and retroviruses.
Human T-cell lymphotropic virus type I (HTLV-I) is a retrovirus that resides in and functionally alters immune cells of central importance for immunoregulation (Fig. 1). First, HTLV-I infects activated T cells and incorporates into their genome, where it persists; second, HTLV-I regulatory proteins alter activation and cell death pathways in the host T cell; third, HTLV-I-infected T cells may activate resting T cells, facilitating propagation of the infection; and finally, HTLV-I infection induces a strong antiviral immune response, which nonetheless appears incapable of eradicating the infection.
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In a small percentage of infected individuals, HTLV-I causes disease (121), most often either adult T-cell leukemia/lymphoma (ATL) or a chronic inflammatory disease of the central nervous system (HTLV-I-associated myelopathy/tropical spastic paraparesis, HAM/TSP). Less frequently, the joints (HTLV-I arthropathy), the eyes (HTLV-I uveitis), the skin (infective dermatitis in children), the muscles (polymyositis), or the lungs (pulmonary infiltrative pneumonitis) are affected (90). While the pathogeneses of these diseases are unknown, they all appear to involve activated, HTLV-I-infected CD4+ T cells.
In this review the interaction between HTLV-I and the cellular immune system is analyzed, with special emphasis on the multiple ways in which HTLV-I maintains an active immune system that favors viral dissemination.
INFECTION OF T CELLS BY HTLV-I
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HTLV-I particles form by budding through the host cell membrane, thereby incorporating cell membrane molecules into the viral envelope. Free HTLV-I particles have extremely low infectivity (314), and transmission of HTLV-I usually requires virus-producing T cells, which allow cell-to-cell contact. The presence of 3'-azido-3'-deoxythymidine at the time of infection appears to have a protective effect on uninfected peripheral blood mononuclear cells (192). Although the receptor for HTLV-I is unknown, a putative receptor or cofactor for HTLV-I entry is thought to be encoded by a gene on chromosome 17 (273). Indirect evidence for this comes from studies with mouse-human somatic cell hybrids infected by a vesicular stomatitis virus (VSV)/HTLV-I pseudotype virus. This chimeric virus is made up of the HTLV-I envelope and the VSV core particle and therefore displays tropism identical to HTLV-I but cytopathic effects like those of VSV. Whereas mouse cells are much more resistant to HTLV-I infection than are human T cells, mouse-human somatic hybrid cells containing a region of the long arm of human chromosome 17 displayed increased susceptibility to infection by the VSV/HTLV-I pseudotype virus (273). The region on chromosome 17 has been mapped to 17q21-q23 (282), although the gene encoding the cofactor or receptor for HTLV-I entry is still unknown.
The core particle of HTLV-I carries two copies of genomic RNA as well as viral enzymes (reverse transcriptase, protease, RNase H, and integrase), which are essential for establishing the viral infection. Upon viral entry into the T cell, RNA is reverse transcribed into DNA and integrates in the host cell genome as a provirus. Although insertion of HTLV-I into the host cell DNA may have a slight preference for G+C-rich regions (325), HTLV-I does not incorporate at specific sites in the genome (260). The integrated HTLV-I provirus consists of 9,032 bp (261) and is organized in 5' and 3' long terminal repeats (LTR), a gag region encoding the structural proteins, a pol region encoding the reverse transcriptase, an env region encoding the envelope proteins, and a region at the 3' end of the provirus known as pX, encoding regulatory proteins (reviewed in reference 74), which are responsible for the altered host cell functions (Fig. 2).
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In vivo, the vast majority of HTLV-I provirus is found in CD4+ CD45RO+ T cells (240, 246) although CD8+ T cells can also be infected (105, 246, 309). Infection of dendritic cells has been demonstrated (191), but its importance in propagating the viral infection has been difficult to evaluate because of the complicated technical procedures involved in obtaining uncultured dendritic cells. Likewise, it has been reported that glial cells can be productively infected in vivo (173). Although this is a potentially important observation, its significance is not clear (215). HTLV-I transcription is higher in primary CD4+ T cells than in CD8+ T cells, which may explain why HTLV-I-induced leukemia and lymphoma are of the CD4+ phenotype (222). It is not known, however, what restricts the viral tropism to predominantly CD4+ T cells, since a broad range of cell types can be infected in vitro. These cell types include B cells (61), monocytes/macrophages (58, 116, 162), NK cells (187), glial cells (116, 303), endothelial cells (115, 126), promyelocytic HL-60 cells (114), and a human osteosarcoma cell line (46). Moreover, coinfection with HTLV-I and human immunodeficiency virus (HIV) broadens the spectrum of HIV cellular tropism to include CD8+ T cells, B cells, epithelial cells, and skeletal muscle cells (190).
A number of reports have described antibodies that interfere with HTLV-I syncytium formation and infection. An antibody known as 34-23 recognizes proteins of 31, 45, 55, and 70 kDa and shows increased binding to mouse-human hybrid cells containing human chromosome 17 (86). Inhibition of HTLV-I syncytium formation and infection was also achieved by an antibody to an 80-kDa glycoprotein (2). However, it is important to bear in mind that antibodies to adhesion molecules may inhibit HTLV-I infection because of interference with cell-cell contact. Recently, an antibody to vascular cell adhesion molecule 1 (VCAM-1) has been shown to prevent HTLV-I syncytium formation, although antibodies to its ligand, very late antigen 4 (VLA-4), did not (111). Moreover, cell-to-cell fusion is not sufficient to ensure viral entry (250). By examining the infectivity of HTLV-I with point mutations in the envelope glycoprotein, Rosenberg et al. (250) defined fusion-competent mutants with severe defects in infectivity. This suggests that the viral envelope glycoprotein may be involved in postfusion events required for full infectivity of HTLV-I.
Incorporation of HTLV-I into the CD4+-T-cell genome may result in either a silent or a productive infection. A silent infection is defined by the presence of HTLV-I sequences in the host cell genome in the absence of detectable HTLV-I-encoded mRNA. Thus, if the virus does not insert into critical genes, a nonproductively infected T cell is functionally indistinguishable from an uninfected T cell. Alternatively, CD4+ T cells may be productively infected by HTLV-I, resulting in viral mRNA transcription and the production of viral particles. Nevertheless, most infected T-cell clones contain a single integrated provirus, indicating that they do not reinfect themselves (247).
Single-cell cloning under limiting-dilution conditions of T cells from HAM/TSP patients indicated a frequency of HTLV-I-infected T cells between 15 and 18%, as determined by PCR amplification of pol or LTR viral sequences from genomic DNA (124, 247, 309). Unless the single-cell cloning is performed with allogeneic, uninfected feeder cells, the frequency is overestimated because of in vitro infection of the T cells (247, 309). The frequency estimate by single-cell cloning is in accordance with independent estimates by limiting-dilution PCR analysis, as well as by Southern blot analysis of genomic DNA from peripheral blood T cells (246). Since most infected T-cell clones contain a single integrated provirus (247), these analyses indicate that HAM/TSP patients have between 3 and 30% (typically 10%) HTLV-I-infected leukocytes. The majority of HTLV-I-infected T cells are silently infected (124, 246, 247, 309), and very few cells (1 in 5,000) express high levels of HTLV-I in vivo (91). It is not clear whether silently infected T cells may later reactivate viral transcription in vivo.
ACTIVATION OF HTLV-I-INFECTED T CELLS
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Activation of the host T cell by HTLV-I occurs through several independent mechanisms, the most intensively studied of which is mediated through activation of cellular transcription factors by the viral trans-activator Tax. Activation of transcription factors may be viewed as the "end" signal of a transduction cascade from the membrane to the nucleus during activation, although a pathway may activate multiple transcription factors and, conversely, a transcription factor may be activated by multiple pathways. Molecular aspects of transcriptional activation by Tax have been reviewed recently (27) and are only summarized here in the context of a signaling pathway activated by HTLV-I.
Besides activation of transcription factors, HTLV-I alters signaling pathways. Typically, T-cell activation requires two signals: an antigen-specific signal mediated via the T-cell receptor (TCR) and a non-antigen-specific costimulatory signal. These signals initiate transcriptional activation of a number of genes and drive the T cell into the mid- to late G1 phase of the cell cycle, the completion of which requires cytokine signaling. HTLV-I regulatory proteins interfere with the control of each of these steps during T-cell activation.
T-Cell Receptor-Mediated Activation
Although infection by HTLV-I may lead to organ-specific inflammatory diseases, the mechanisms that target tissue destruction to the central nervous system, the joints, the eyes, the muscles, etc., are unknown (118). It is conceivable, though, that autoreactive T cells are randomly infected and cause organ-specific disease by virtue of their chronic activation and altered requirements for antigen-specific triggering (118). This hypothesis is difficult to test because of the inherent problems of generating antigen-specific T-cell clones from HTLV-I-infected individuals. That is, since mononuclear cells from these patients undergo spontaneous proliferation following 3 to 9 days in culture (133, 139), it is virtually impossible to determine antigen-specific responses, because the "background" of spontaneous proliferation often amounts to more than that of an antigen-specific response.
Recent advances in generating MHC-peptide complexes and peptide-loaded soluble MHC class I-immunoglobulin complexes make it feasible to directly isolate antigen-specific T cells (11, 101). This approach may clarify the possible role of antigen-specific T cells in HTLV-I-induced diseases. So far, however, the only way to analyze the impact of HTLV-I infection on antigen-specific T-cell responses relies on in vitro infection of established antigen-specific T-cell clones. Mitsuya et al. (206) examined the functional properties of tetanus toxoid-specific T cells infected by HTLV-I. The HTLV-I-infected T-cell clones proliferated in response to soluble tetanus toxoid, but, unlike uninfected T-cell clones, they could do so in the absence of accessory cells. This may be explained by upregulation of MHC class II on HTLV-I-infected T cells (276) followed by T-cell presentation of antigen. Thus, Scholz et al. (256) found that an HTLV-I-infected T-cell clone specific for a myelin basic protein peptide responded to an approximately 100-fold-lower concentration of soluble peptide antigen than did the parental uninfected T-cell clone. The mechanism of the enhanced response involved upregulation of MHC class II and lymphocyte function-associated antigen 3 (LFA-3; CD58) on the infected T cells, which allowed them to present the peptide antigen to other T cells. Nevertheless, compared to uninfected T cells, the response of HTLV-I-infected T cells to antigenic peptide presented by Epstein-Barr virus (EBV)-transformed B cells was slightly impaired. This demonstrated that the responsiveness of the HTLV-I-infected T cells was not enhanced; rather, the HTLV-I-infected T cells were better antigen-presenting cells (APCs).
Popovic et al. (239) examined the consequences of infecting
a keyhole limpet hemocyanin (KLH)-specific CD4+ T-helper
cell (SR2) with an HTLV-I-infected isolate (TK). SR2 cells proliferated
and provided "help" to B lymphocytes in the presence of KLH
presentation in the context of the appropriate MHC class II. However,
following HTLV-I infection, TK-infected SR2 cells displayed spontaneous
proliferation in the absence of antigenic peptide. Importantly, the
TK-infected SR2 cells gained the ability to provide promiscuous
antigen-independent help to B cells, resulting in polyclonal
immunoglobulin production. The mechanism of the promiscuous B-cell help
was not examined, but interleukin-4 (IL-4), IL-5, and gamma interferon
(IFN-
) are known to enhance immunoglobulin secretion, and these
cytokines were spontaneously secreted by a myelin basic
protein-specific HTLV-I-infected T-cell clone (255).
Nevertheless, Yarchoan et al. (318) found that supernatant
from an infected T-cell clone, 8.8H, which provided promiscuous
antigen-independent B-cell help, did not provide help for
immunoglobulin production. Although this may not entirely rule out
cytokines, it suggests that cognate T-cell-B-cell interaction is
required for the promiscuous B-cell help provided by HTLV-I-infected T cells.
In contrast, loss of function was demonstrated in two alloreactive
cytotoxic CD4+-T-cell clones. Following infection, the
number of HTLV-I p19-expressing T cells increased concomitantly with a
loss of cytotoxicity (239). Although it was not shown that
the HTLV-I-infected T cells were of the same origin as the parental
cytotoxic T-cell clone, the observation suggested that HTLV-I infection
interfered with the cytotoxic effector mechanism. Subsequent studies
confirmed the loss of cytotoxicity in antigen-specific HTLV-I-infected
T cells (131, 277, 318, 322) and additionally provided
evidence for identical 
-chain rearrangement of the TCR in the
infected T-cell clones with impaired cytotoxicity and their parental
uninfected T-cell clones, indicating that they were of the same origin
(131, 277, 322).
During the early phase after HTLV-I infection, the expression of CD2,
CD3, CD4, CD26, and CD28 remains normal whereas the expression of the
IL-2 receptor 
(IL-2R) chain and human leukocyte antigen (HLA)-DR
is upregulated (276, 322). Following this stage, the
HTLV-I-infected T cells may become IL-2 independent (i.e., transformed). This is usually accompanied by downregulation of CD3
expression and loss of antigen responsiveness (131, 322). Nevertheless, the loss of cytotoxic activity may be an effect on the
lytic machinery, since HTLV-I-infected T cells had lost serine esterase
activity (322) and since the loss of cytotoxic function
occurred with normal levels of CD3 expressed on the cell surface
(131).
In summary, complex alterations may influence the antigen response of
HTLV-I-infected T cells and lead to both gain of function and loss of
function: CD4+ T-helper cells may gain APC-like functions
and the ability to provide indiscriminate B-cell help, whereas
cytotoxic CD4+ T cells may lose their cytotoxic effector
function (Table 1).
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Recently, Mahana et al. (194) demonstrated that the
phosphorylation state of the protein Vav can be influenced by
proteins from the pX region of HTLV-I. Using molecular
clones, they were able to associate the ability of an infected T-cell
clone to induce asymptomatic infection with a downregulation of Vav
phosphorylation. In contrast, a T-cell clone which induced lethal
leukemia differed in two nucleotides in the pX region and displayed
constitutive tyrosine phosphorylation of Vav. Since
tyrosine-phosphorylated Vav is involved in the signal transduction from
the TCR, this suggests the possibility
contrary to the general
assumptionthat minor differences in the HTLV-I sequence may be
important in the pathogenesis.
PKA signaling pathway. The second-messenger cyclic AMP (cAMP) influences T-cell signaling via a cAMP-dependent protein kinase (PKA). PKA is composed of two catalytic (C) subunits and two regulatory (R) subunits, which exist in two isoforms, giving rise to type I and type II PKA. Each regulatory subunit can bind cAMP at two distinct binding sites, which dissociates the PKA complex into R2(cAMP)4 and two catalytically active C subunits. Since type I PKA is dissociated more easily than type II PKA and since the localization of the isotypes may differ (for example, type I PKA colocalizes with the TCR, in contrast to type II PKA), differential activation of the two types of PKA may shape the response of a given cell to a variety of stimuli. Thus, it has been suggested that type I PKA is involved in the response to proliferative signals whereas type II PKA is involved in cell differentiation and the response to antiproliferative signals (44).
Activation of the catalytic subunit of PKA leads to phosphorylation of cAMP response element (CRE) binding proteins (CREBs) on Ser-133. In addition to cellular CREs, a CRE-like domain is found in each of three 21-bp imperfect repeats in the HTLV-I LTR promoter, which are known as the Tax responsive elements. Tax-mediated transactivation of the viral LTR occurs through interaction with the CREB/activating transcription factor (ATF) family of proteins (1, 278, 319). In vitro, Tax also interacts with and facilitates dimerization of other basic-region leucine zipper (bZIP)-containing proteins, thereby enhancing their DNA binding activity (16, 235, 299), although this may not be important in vivo. Tax may activate both cellular CREs and HTLV-I LTR CREs, although the mechanisms of transactivation of these CRE sites differ (319). Murine thymoma cell lines deficient in either the catalytic subunit (lacking PKA activity) or in the adenylate cyclase (lacking endogenous cAMP, but with normal PKA) were used to evaluate the significance of the PKA signaling pathway on Tax transactivation (146, 241). Whereas the response of the viral LTR to cAMP depended on PKA, the Tax-mediated transactivation of the LTR did not require PKA activity. Nevertheless, Tax-induced transactivation decreased in the absence of PKA activity and was restored by the catalytic subunit of bovine PKA. Moreover, a single-amino-acid substitution in CREB at Ser-133, an essential phosphorylation site for transcriptional activation, attenuated both Tax- and PKA-mediated activation of the HTLV-I promoter (26). In contrast, Kwok et al. (164) found that mutation of Ser-133 in CREB did not impair Tax-mediated transactivation of the LTR but significantly impaired Tax-mediated transactivation of cellular CREs. The difference between the HTLV-I CREs and cellular CREs may be explained by a differential requirement for CREB phosphorylation in recruiting CREB binding protein. Thus, association of Tax with cellular CRE occurs through CREB binding protein, which is recruited only in the presence of phosphorylated CREB. In contrast, Tax-mediated activation of viral CRE may occur in the absence of CREB phosphorylation (164). CRE, together with serum response elements, is also involved in Tax-mediated activation of immediate-early genes, including c-fos, fra-1, c-jun, junD, erg-1, and erg-2 (9, 77, 78). Tax mediates activation through interaction with the serum response factor p67SRF (79, 279). Consistently, constitutively high-level expression of c-Fos (10, 77), Erg-1, and Erg-2 (9, 77) has been found in HTLV-I-transformed T cells and Tax-expressing cell lines. This provides a mechanism by which Tax may in part replace growth signals in HTLV-I-infected T cells.PKC signaling pathway.
Activation of T cells through
the TCR but not through the IL-2R (295) results in protein
kinase C (PKC) activation (reviewed in reference
281). The family of PKC isoenzymes includes at least 12 members, some of which are not Ca2+ dependent. PKC
isoenzymes are usually divided into three groups based on their primary
structure and their activation requirements: (i)
Ca2+-dependent or conventional PKCs (PKCs) include PKC-,
PKC-1, PKC-2, and PKC-; (ii) Ca2+-independent or
novel PKCs (PKC) include PKC-
, PKC-
, PKC-
, PKC-
, and
PKC-µ; and (iii) atypical PKCs (PKCs), which do not respond to
phorbol esters, include PKC-
, PKC-
, and PKC-
(32, 281).
, PKC-, and PKC-
(183). The association results in phosphorylation of Tax and
an increase in autophosphorylation of PKC in vitro, indicating that Tax
activates PKC activity. The significance of the phosphorylation of Tax
is unclear (73, 227). However, Tax-mediated activation of
PKC may explain the activation of nuclear factor 
B (NF-B)/Rel in HTLV-I-infected T cells. The NF-B/Rel family of transcription factors includes p50 (NF-B1), p52 (NF-B2), p65 (RelA), c-Rel, and
RelB (185), which occur as dimers sequestered in the
cytoplasm through association with NF-B inhibitor proteins IB,
IB, IB, IB, and Bcl-3. In addition, p100 (NF-B2)
and p105 (NF-B1), precursors of p52 and p50, respectively, possess
IB domains (266). Following T-cell activation, NF-B
separates from IB and translocates to the nucleus. The NF-B/IB
dissociation is thought to occur following phosphorylation of IB,
but dephosphorylation of IB may also be involved in NF-B/Rel
activation (184). Calphostin C, a PKC inhibitor, prevented
both phorbol ester- and Tax-induced NF-B DNA binding activity
(183). Moreover, transfection of Jurkat T cells with a Tax
mutant (M22) that fails to activate NF-B-dependent transcription
failed to induce membrane translocation of PKC (183). Tax
did not appear to increase PKC phosphorylation of IB, suggesting the possibility that Tax activates the PKC pathway and that downstream events lead to phosphorylation of IB and subsequent NF-B
activation. A role for Tax in activating signal transduction pathways
upstream of IB was also suggested by Kanno et al.
(149), who found that IB mutants which were defective
in extracellular signal-induced degradation also blocked Tax-mediated
NF-B activation. Recently, several IB kinases have been
identified (62, 172, 200, 245, 258, 308, 323), and Tax may
also associate with and activate these kinases (45, 88).
It has also been demonstrated that Tax may activate the NF-B/Rel
system by direct interaction with its members. Thus, Tax was found to
activate NF-B/Rel by associating with ankyrin motifs in IB
(113) and by interacting directly with different NF-B/Rel members, including p50 (279), p65 (166), p100
(20, 171), and c-Rel (171). Tax has also been
reported to transactivate the c-rel promoter, leading to
increased c-Rel expression (179).
Collectively, these data suggest that Tax may use several mechanisms to
activate NF-B/Rel proteins: (i) by activation of PKC, (ii) by
interaction with NF-B/Rel and IB proteins, and (iii) by
activation of IB kinases.
Activation of NF-B has been implicated in HTLV-I-induced
tumorigenesis, since the growth of both the HTLV-I-transformed T-cell line MT-2 and of fibroblastic tumors in Tax transgenic mice were inhibited by antisense oligodeoxynucleotides to mRNA of either p50 or
p65 (155).
The requirements for Tax-mediated transactivation of the CREB/ATF or
NF-B/Rel pathways can be separated. Smith and Greene (271) generated Tax mutants by site-directed mutagenesis
affecting two consecutive codons. Tax mutants that selectively induced
either CREB/ATF but not NF-B/Rel activity or NF-B/Rel but not
CREB/ATF activity could be defined. Similarly, Semmes and Jeang
(263) generated 47 single-amino-acid Tax mutants and
analyzed their transactivation ability, confirming the observation by
Smith and Greene that Leu320 was important for CREB/ATF
activity but not for NF-B/Rel activity. Both studies indicated that
the N-terminal 50 amino acids and a C-terminal region between amino
acids 275 and 325 are important for the transactivating function of
Tax. Using Tax mutants deficient in inducing either CREB/ATF or
NF-B/Rel activity, Smith and Greene found that transformation of rat
fibroblasts was achieved by transfection of Tax or by transfection of a
Tax mutant deficient in activation of NF-B/Rel but not by
transfection of a Tax mutant deficient in activation of CREB/ATF
(272); suggesting that CREB/ATF, but not NF-B/Rel, was
critical for Tax-mediated transformation of rat fibroblasts. Since this
appears to be in conflict with the data from Tax transgenic mice
(155), it is likely that cell-specific factors determine the
relative importance of CREB/ATF and NF-B/Rel in transformation.
Thus, the role of CREB/ATF and NF-B/Rel proteins in the induction of
ATL is unclear.
Ca2+ signaling pathway.
Activation of
NF-B/Rel or CREB/ATF is not sufficient for Tax-mediated activation
of the CD28 enhancer of the IL-2 gene. LiFeng et al. (181)
found that nuclear factor of activated T cells (NF-AT) complexes
induced by Tax bound to the CD28 response element in the IL-2 promoter,
implicating NF-AT in Tax-mediated transactivation. In contrast to the
cooperation between NF-AT and the transcription factors c-Fos and c-Jun
(AP1) (242), the Tax-induced NF-AT complex does not contain
c-Fos or c-Jun (181). Moreover, constitutive dephosphorylation and activation of NF-ATp, a member of the NF-AT family, was found in Tax-expressing and HTLV-I-infected T-cell lines (180). The constitutive dephosphorylation of NF-ATp
was reversed in the presence of cyclosporin A (CsA), an inhibitor of
the calcium/calmodulin-dependent phosphatase calcineurin. This suggests
that Tax activates the Ca2+ signaling pathway proximal to
or at the level of calcineurin. Interestingly, activation of the
Ca2+ signaling pathway downregulates IL-10 production. In
particular, the combination of Ca2+ ionophores and phorbol
esters results in poor IL-10 induction but significant IFN-
production (321). Indeed, HTLV-I infection of an
IL-10-producing T-cell clone resulted in a loss of its ability to
secrete IL-10 but in acquisition of the ability to constitutively secrete IFN- (256). In contrast, transfection of Jurkat T
cells with a Tax expression plasmid induced IL-10 mRNA expression and IL-10 secretion (213), and this was partially inhibited by
antisense oligonucleotides to the p65 subunit of NF-B. The reason
for this discrepancy in IL-10 secretion between Tax-transfected Jurkat T cells and HTLV-I-infected T-cell clones is unclear, but a similar discrepancy in IL-2 secretion can be found between these cells (124, 199), suggesting that the level of expression of Tax
or of other viral or cellular proteins may explain the difference.
MAP kinase pathways. At least three pathways have been delineated via the small GTPases Ras, Rac, CDC42, and Rho. Ras activates extracellular signal-regulated kinases 1 and 2 (ERK-1 and ERK-2) via Raf and mitogen-activated protein (MAP) kinase/ERK kinase 1 and 2 (MEK-1 and MEK-2); Rac and CDC42 activate c-Jun N-terminal kinase (JNK) via p21-activated kinase (PAK), MEK kinase (MEKK), and JNK kinase; and Rho activates p38 via a less well characterized pathway. However, cross talk between the pathways exists; Ras may activate JNK, and CDC42 and Rac may activate p38 (reviewed in reference 182).
The transition from IL-2-dependent to IL-2-independent growth in HTLV-I-infected T cells is associated with constitutive activation of JNK (142, 311). A downstream target of JNK is the transcription factor ATF2, which, together with CREB, is important for activation of the HTLV-I promoter (75). Thus, activation of the JNK pathway by Tax helps to increase the transcription of HTLV-I. The mechanism of JNK activation was examined by Jin et al. (142), who identified a novel protein, named G-protein pathway suppressor 2 (GPS2), which interacted physically with Tax and inhibited its activation of JNK. GPS2 also inhibited tumor necrosis factor alpha (TNF-) activation of JNK. In contrast, GPS2 did not
prevent TNF--induced activation of p38, nor did it prevent MEKK- or
JNK kinase-mediated JNK activity (142).
This indicates that GPS2 acts between the TNF- receptor and MEKK and
hence suggests that Tax-induced activation of the MAP kinase pathway
occurs proximal to MEKK, perhaps via Ras,
phosphatidylinositol-3-kinase, Rac, or PAK (Fig.
3).
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Costimulatory Signaling Pathways
Several signaling pathways and transcription factors involved in TCR-CD3 signal transduction are activated in HTLV-I-infected T cells. However, while separate surface receptors may activate a distinct set of kinases, signaling pathways often converge on a common pathway. Hence, the presence of activated proteins in a common pathway is compatible with activation of several upstream pathways. This becomes an issue when analyzing the evidence for activation of costimulatory pathways in HTLV-I-infected T cells, since the membrane-proximal signaling molecules in these pathways have not been well defined.
CD28 costimulation. A number of molecules expressed on T cells may enhance or costimulate T-cell activation; however, special emphasis has been placed on the CD28 molecule, since mice deficient in the CD28 gene have significantly impaired T-cell activation (98). This indicates that other costimulatory pathways cannot completely compensate for the loss of CD28 signaling (98). The salient functions of the CD28 costimulatory pathway are to enhance IL-2 transcription, stabilize IL-2 mRNA, and promote T-cell survival by upregulating the antiapoptotic protein Bcl-xL (274).
The CD28 signaling pathway is resistant to inhibition by CsA but sensitive to rapamycin (22, 145), a phenotype also observed for the IL-2R pathway (66). Nontransformed and nonimmortalized HTLV-I-infected T-cell clones were resistant to CsA and sensitive to rapamycin (124), consistent with virus-mediated activation of either the CD28 or IL-2R signaling pathway. The CD28 ligands, CD80 and CD86, are upregulated on HTLV-I-infected T cells (169, 255, 296), suggesting the possibility that the CD28 signaling pathway is constitutively active. The CD28 costimulatory requirements of HTLV-I-infected T cells were analyzed by comparing an HTLV-I-infected, antigen-specific T-cell clone with the uninfected parental T-cell clone (255). As APCs, Chinese hamster ovary (CHO) cells transfected with the restricting MHC class II element alone or in combination with CD80 or CD86 were used. These experiments demonstrated that the HTLV-I-infected T-cell clone was independent of CD80 or CD86 costimulation for proliferation and for IL-5 and IFN-
secretion, in contrast to the uninfected T-cell clone (255).
Moreover, the presence of antibodies to CD80 and CD86 prevented
proliferation induced by CD80- or CD86-transfected CHO cells in
uninfected but not HTLV-I-infected T cells (255). Similarly,
Tax-transduced or Tax-transfected T cells cooperate with CD3-mediated
activation, suggesting that Tax modulates the same costimulatory
pathway as does CD28 signaling.
Taken together, these observations suggest that HTLV-I-induced T-cell
activation substitutes for CD28 costimulation. However, CD80- or
CD86-induced costimulation is a potent inducer of IL-2 mRNA, but
HTLV-I-infected T-cell clones (124) and Tax-transduced primary T cells (8) did not express IL-2 mRNA by Northern
blotting analysis. Thus, the FK506- and CsA-resistant and
rapamycin-sensitive pathway is more likely to involve the IL-2R pathway
(late CD28 pathway) than the early CD28 pathway.
CD2 costimulation. The CD58-CD2 interaction is important for activation of resting and uninfected T cells by HTLV-I-infected T cells (152, 153, 309), as discussed later in this review. However, the CD2 pathway is not critical for HTLV-I-induced activation of infected T-cell clones, since FK506 and CsA inhibit the CD2 signaling pathway (22) but not the HTLV-I-induced activation of the host T cell (124).
OX40 costimulation. A contribution from other costimulatory pathways to HTLV-I-induced T-cell activation cannot be excluded. The interaction between OX40, a TNF/nerve growth factor receptor family member, and its ligand, gp34 (OX40L), is costimulatory for T cells in the presence of mitogens (18, 94). OX40L was initially detected on HTLV-I-infected T cells as a 34-kDa glycoprotein transactivated by Tax (207, 286, 291). OX40 is induced on activated T cells and constitutively expressed on HTLV-I-transformed T cells (130); nevertheless, the significance of the OX40-OX40L interaction for HTLV-I-induced T-cell activation remains to be determined. Since OX40 mediates adhesion to OX40L expressed on vascular endothelial cells (129, 130), it is possible that this interaction is important for HTLV-I-mediated inflammatory diseases.
IL-2R Signaling Pathway
In normal T cells, the cytokine IL-2 induces the
G1-to-S phase transition (36). Since this is
essential for T-cell cycling, there has been interest in the
possibility that HTLV-I-infected T cells use an IL-2 autocrine
mechanism to traverse the G1 restriction point. The
high-affinity IL-2R complex is composed of three subunits: the ,
c, and c chains; the subscript c
indicates that these chains are shared (common) among several cytokine
receptors: c is used by IL-2R and IL-15R;
c is used by IL-2R, IL-4R, IL-7R, IL-9R, and IL-15R
(reviewed in reference 287). The signaling module of
the IL-2R comprises cc, which itself is
an intermediate-affinity IL-2R. The IL-2R chain does not participate
in signal transduction, but its association with
cc increases the receptor affinity for
IL-2 by approximately 100-fold (287).
The possibility that HTLV-I particles or surface proteins can activate
the IL-2R pathway was initially suggested based on an association
between HTLV-I virions and the IL-2R chain (170); furthermore, it was shown that the HTLV-I envelope glycoprotein contains a region homologous to a segment of IL-2 that binds
c (160). Whether these features of the HTLV-I
virion are important for activation of the IL-2R signaling pathway
remains to be demonstrated.
The IL-2R chains are absent or expressed at very low levels in resting
T cells, but their expression is inducible upon T-cell activation
(53). IL-2R chains are expressed in large numbers on
HTLV-I-transformed T cells from patients with ATL (107). The mechanism involves Tax transactivation of the promoter for the IL-2R
chain (50, 132, 197, 268) and is mediated by activation of
NF-B (15, 176, 252). In addition, transient-transfection studies linking the promoter of IL-2 to a chloramphenicol
acetyltransferase (CAT) reporter gene demonstrated that Tax may also
transactivate the IL-2 promoter (132, 197, 199, 268).
Although the Tax-mediated transactivation of the IL-2 promoter is not
very strong, it may synergize with a TCR- or phorbol ester-mediated
signal or with the HTLV-I regulatory protein Rex (197, 199).
Nonetheless, analysis of IL-2 secretion and IL-2 mRNA in
HTLV-I-infected T-cell lines or clones has not implicated IL-2
autocrine growth in HTLV-I-induced T-cell activation. Arya et al.
(14) did not detect IL-2 mRNA expression in
HTLV-I-transformed T cells (HuT-102) by Northern blot hybridization of
cloned IL-2 DNA to poly(A) isolated RNA. Likewise, Northern blot
analysis of HTLV-I-infected T-cell clones at a time when they displayed
spontaneous clonal proliferation did not detect IL-2 mRNA
(124). Moreover, the presence of a blocking antibody to the
IL-2R chain (anti-Tac) did not prevent the HTLV-I-induced
proliferation (124). The transcription factor NF-AT is
important for the initiation of IL-2 gene transcription, and CsA and
FK506 inhibit IL-2 production by preventing the dephosphorylation and
nuclear translocation of NF-AT. CsA or FK506 did not inhibit the
spontaneous clonal proliferation of HTLV-I-infected T-cell clones,
although they did inhibit TCR-CD3-mediated superimposed proliferation
of these clones (124). CD28-induced signals may, however,
activate NF-AT and lead to IL-2 secretion in a CsA-resistant manner
(92), and CsA may not inhibit Tax-induced transactivation of
the IL-2 gene (268).
Taken together, however, the data on HTLV-I-infected T-cell clones suggest that autocrine IL-2 secretion is not involved in HTLV-I-induced spontaneous clonal proliferation. In addition, Akagi and Shimotohno (8) found IL-2-independent proliferation of Tax-transduced T cells after CD3 cross-linking.
To investigate IL-2 mRNA expression in single cells, Goebels et al.
(95) examined three HTLV-I-transformed T-cell lines by in
situ hybridization with an IL-2 cRNA probe. Whereas 2% of HuT-102,
0.8% of MT-2, and 0.5% of MT-4 HTLV-I-transformed T-cell lines
expressed IL-2 mRNA, 28 to 35% of uninfected but phorbol myristate
acetate- and phytohemagglutinin-stimulated Jurkat T cells expressed
IL-2 mRNA. Moreover, using a system with inducible expression of an
endoplasmic reticulum-targeted single-chain antibody to knock out
surface expression of IL-2R, Richardson et al. (248) found that IL-2R expression is dispensable for in vitro growth of
HTLV-I-transformed T-cell lines. Thus, proliferation of
HTLV-I-transformed T cells is not mediated by autocrine IL-2 secretion.
A more complex question is the role of the IL-2R pathway during the transformation process. The lack of detectable IL-2 mRNA in HTLV-I-infected T-cell clones, which are neither completely immortalized nor transformed, suggests that the transformation is not the direct result of aberrant autocrine IL-2 secretion. Nevertheless, this does not exclude an important role of the IL-2-IL-2R pathway in the early phase following HTLV-I infection. Kimata and Ratner (153) examined the presence of IL-2 mRNA and IL-2 activity following HTLV-I infection of human primary lymphocytes. While IL-2 was transiently expressed during the early phase of the infection (days 7 to 49, when viral integration is polyclonal), it was undetectable at later stages (days 100 to 150, when viral integration is oligoclonal). In contrast, expression of the viral tax-rex mRNA was low in the polyclonal phase and high in the oligoclonal phase, indicating that Tax expression did not induce autocrine IL-2 secretion. Indeed, the source of IL-2 during the polyclonal phase of the infection is uncertain, since HTLV-I-infected T cells can induce IL-2 production from uninfected T cells via T-cell-T-cell interaction (152, 310). In summary, evidence supporting a critical role for an autocrine IL-2 growth loop in HTLV-I-induced T-cell transformation is lacking.
Importantly, the development of IL-2 independence (i.e.,
transformation) may be associated with a constitutive IL-2-independent activation of the IL-2R signaling pathway. The ability of IL-2 to
induce a signal in T cells is due to dimerization of the
c and c chains and subsequent
phosphorylation of signal transduction proteins. IL-2R signaling
involves tyrosine phosphorylation and activation of the Janus family of
kinase 1 and 3 (JAK1 and JAK3), which are associated with the
c and c chains, respectively. Upon
activation, JAKs phosphorylate tyrosine residues in the cytoplasmic tail of the IL-2R, which serve as docking sites for latent cytoplasmic transcription factors termed signal transducers and activators of
transcription (STATs). STATs are then tyrosine phosphorylated and
activated by JAKs, resulting in dimerization and nuclear translocation of STATs (52). IL-2R signaling activates STAT5 in resting T cells and activates STAT1, STAT3, and STAT5 in preactivated T cells. In
contrast to nontransformed HTLV-I-infected T cells and Tax-transfected
T cells, HTLV-I-transformed T-cell lines displayed constitutive
tyrosine phosphorylation of JAK3 (202, 312), JAK1, STAT3,
and STAT5 (202). In addition, STAT3 and STAT5 displayed constitutive DNA binding activity, and both c and JAK3
associated with the IL-2R c, indicating an activated
IL-2R signaling pathway in the absence of IL-2 (202).
HTLV-I-infected but nonimmortalized and nontransformed T-cell clones expressed slightly elevated levels of JAK3 and STAT3 tyrosine phosphorylation but showed diminished induction of further tyrosine phosphorylation following IL-2 stimulation (255). Importantly, uncultured leukemic cells from patients with ATL expressed constitutive tyrosine phosphorylation, constitutive DNA binding activity, or both, of one or more of JAK3, STAT1, STAT3, STAT5, and STAT6, and there was a correlation between proliferation of ATL cells and activation of JAK3, STAT1, STAT3, and STAT5 (284). Since JAK1/JAK3 and STAT3/STAT5 activation is not observed in Tax-transfected T cells or newly HTLV-I-infected cord blood T cells (202), the constitutive activation of JAK and STAT may be associated with the process of transformation. In support of this notion, the transition to IL-2-independence of HTLV-I-infected cord blood T cells occurred concomitantly with an increase in constitutive STAT activity (202). Despite this association, the mechanism of JAK and STAT activation has not been linked to a viral protein yet.
A candidate viral protein that may induce IL-2R activation is
p12I, which may be encoded by the first open reading frame
(ORF) of the pX region of HTLV-I (161) (Fig. 2). When
overexpressed, p12I physically associates with both the
c and c chains (216) and may
dimerize them, thereby initiating constitutive JAK and STAT activation
and IL-2-independent proliferation (i.e., transformation). Nonetheless,
alternatively spliced mRNAs of ORF-I (encoding p12I) can be
found in both IL-2-independent and IL-2-dependent HTLV-I-infected T-cell lines with significant variability between cell lines
(38). Although the variability in the level of
p12I mRNA may indicate that splice site regulation is an
important viral regulatory pathway, it also suggests that
transformation cannot be explained simply by a shift in splice site
utilization to ORF-I. However, it is clear that p12I is not
necessary for immortalization of HTLV-I-infected T cells, since
deletion of ORF-I and ORF-II in an infectious molecular clone does not
affect its ability to immortalize T cells (59), and,
furthermore, Tax is both necessary and sufficient for in vitro
immortalization of primary human CD4+ peripheral and cord
blood lymphocytes (8, 96, 97). However, these
Tax-immortalized T cells remain IL-2 dependent (8, 96), suggesting a possible role for additional proteins in the
transformation process.
In summary, autocrine IL-2 production may play a role early after infection, causing clonal expansion, but its production diminishes and little if any IL-2 is produced at later stages in the nontransformed, HTLV-I-infected T cell. Concomitantly with transformation, however, activation of the JAK-STAT pathway of the IL-2R is activated by an unknown mechanism.
Besides JAK1 and JAK3, the protein tyrosine kinases Syk, Lck, and Fyn
associate with the IL-2R and contribute to its signal transduction
(106, 156, 204). Lck and Fyn are dispensable for IL-2R-mediated signaling in HTLV-I-infected T cells (203).
The transition from an IL-2-dependent state to an IL-2-independent state (i.e., transformation) in HTLV-I-infected T-cell lines correlated with downregulation of lck mRNA (159) (Table
2), and although IL-2-dependent
HTLV-I-infected T-cell lines expressed lck mRNA, they
scarcely expressed Lck protein (228). Consistently,
Tax-transfected Jurkat T cells expressed diminished levels of Lck
protein and repressed lck mRNA levels (174).
Genes that are known to be repressed by Tax contain binding sites
(E-boxes) for basic helix-loop-helix proteins in their promoter regions
(292, 293). Whereas uninfected T cells may use two separate
promoters for lck transcription, HTLV-I-infected and
IL-2-dependent T cells use the upstream promoter exclusively
(221). Transfection of a CAT construct under control of the
distal lck promoter demonstrated that Tax downregulated this
promoter, but not if a putative E-box was deleted (174). The
Tax-mediated downregulation of lck mRNA was proportional to the level of pX mRNA (174). Conversely, Lck suppresses the
HTLV-I promoter (229), suggesting that downregulation of Lck
may further enhance viral transcription. In contrast to Lck and Fyn,
altered expression of IL-2R-associated Syk in HTLV-I-infected T cells has not been reported. Syk may be a mediator of IL-2-induced activation of c-Myc (204, 208).
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HTLV-I-Induced Cell Cycling
Incorporation of [3H]thymidine in the absence of exogenous IL-2 in HTLV-I-infected but not uninfected T-cell clones indicates that the virus is capable of inducing the G1/S-phase transition. In its hypophosphorylated form, the retinoblastoma protein (pRb) is a negative regulator of the G1/S-phase transition, in part through its sequestering of members of the E2F family of transcription factors (267). Following T-cell activation, pRb is inactivated by phosphorylation and releases E2F, which promotes S-phase entry. During the early G1 phase, cyclins D2 and D3 and cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) are synthesized by an IL-2-independent pathway (189, 209), whereas IL-2 stimulation late in G1 induces de novo synthesis of CDK2 (209), the kinase partner of cyclin E. Initially, D-type cyclin complexes are responsible for pRb phosphorylation, whereas cyclin E-CDK2 becomes the major pRb kinase close to the G1/S-phase transition (267). The activity of cyclin-CDK complexes is regulated by a group of CDK inhibitors, of which two families have been described. One family, including p21WAF1/CIP1, p27KIP1, and p57KIP2, inhibits all CDK-cyclin complexes, whereas the other family, including p16INK4a, p15INK4b, p18INK4c, and p19INK4d, specifically inhibits the kinase activity of cyclin D-CDK4 and cyclin D-CDK6 (244, 267).
HTLV-I-mediated interference with cell cycle-regulating proteins was
initially demonstrated in T-cell clones from patients with HAM/TSP; in
contrast to uninfected T-cell clones, pRb was constitutively
hyperphosphorylated in HTLV-I-infected T-cell clones (119).
The hyperphosphorylation of pRb correlates with Tax expression in a
tetracycline repressor-based Tax expression system (254). Importantly, although transforming growth factor (TGF-)
completely abolished hyperphosphorylation of pRb in CD3-TCR-stimulated,
uninfected T-cell clones, it did not prevent pRb phosphorylation in
HTLV-I-infected T-cell clones (119). These observations
suggest that HTLV-I activates T cells via a TGF--insensitive
pathway. TGF- interferes with pRb phosphorylation by its ability to
(i) induce an inhibitor, p15INK4b, of CDK4 and CDK6
(104); (ii) inhibit CDK4 synthesis (70); (iii)
inhibit CDK2 synthesis (89); (iv) inhibit cyclin A synthesis (89); (v) inhibit cyclin E synthesis (89); and
(vi) prevent the assembly of active cyclin E-CDK2 complexes
(158) by releasing sequestered p27KIP1
(238, 269). Tax does not significantly alter the expression of CDK2, CDK4, CDK6, p27KIP1, or cyclin A (7).
Suzuki et al. (280) and Low et al. (188) found
that Tax associates with p16INK4a. Whereas
p16INK4a inhibits CDK4 kinase activity, the
Tax-p16INK4a complex has lost this function. This provides
direct evidence for Tax-mediated interference with cell cycle
progression (Fig. 4).
p16INK4a contains four ankyrin motifs, and it is possible
that Tax binds to p16INK4a via these motifs, since Tax
binding to IB can be mediated by ankyrin motifs (113). It
remains to be determined whether Tax also inhibits
p15INK4b, a mediator of TGF- inhibition, which is 97%
homologous to p16INK4a in the last three of its four
ankyrin motifs (264). Inhibition of p16INK4a may
explain the Tax-induced activity of CDK4 and CDK6 and thus the ability
of Tax to induce G1- to S-phase progression in lymphocytes (254), although Tax can also activate E2F-mediated
transcription independently of p16INK4a (175).
Tax may also enhance cyclin D-CDK4 activity by decreasing the
expression of p18INK4c (7). Interestingly,
HTLV-I-infected T-cell lines expressed high levels of cyclin D2 mRNA,
in contrast to uninfected T-cell lines, which predominantly expressed
cyclin D3 mRNA (7). The significance of this is unknown. Tax
does not appear to switch the cyclin D isotype from D2 to D3 (7,
254).
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The CDK inhibitor p27KIP1 is a critical regulator of the
G1 restriction point, since (i) IL-2R signaling eliminates
p27KIP1 (72, 165, 226) through a
rapamycin-sensitive pathway (226); (ii) rapamycin-sensitive
cells become rapamycin resistant if p27KIP1 synthesis is
inhibited by antisense oligonucleotides (150); (iii)
antisense inhibition of p27KIP1 synthesis prevents the
cells from becoming quiescent (47, 249); and (iv)
p27KIP1 links TGF- to cell cycle arrest in mink
epithelial cells (238). Despite the central role of
p27KIP1 in cell cycle regulation, it is not known whether
the function of p27KIP1 is altered in HTLV-I-infected T
cells. Low et al. (188) did not detect an association of Tax
with p27KIP1 under conditions where Tax associated with
p16INK4a. Nevertheless, HTLV-I-mediated spontaneous
proliferation is inhibited by rapamycin (124) but not by
TGF- (119). This indicates that p27KIP1
regulation is normal in HTLV-I-infected T-cell clones and hence not
involved in their lack of inhibition by TGF-.
In contrast, the level of the CDK inhibitor p21WAF1/CIP1 is elevated in HTLV-I-transformed T cells by a mechanism involving Tax-mediated transactivation of the promoter for p21WAF1/CIP1 (7, 39), but Tax does not physically associate with p21WAF1/CIP1 (188). The expression of p21WAF1/CIP1 is normally regulated by p53 and is responsible for p53-induced G1 arrest following DNA damage (31, 57), but Tax-induced p21WAF1/CIP1 expression is p53 independent, since it occurs in p53-null cells (39). Despite the presence of the wild-type p53 gene in most HTLV-I-transformed T cells (39), Tax inactivates p53 by inhibiting its transcription (293) and by interfering with its transactivation domain (237). The lack of fully functional p53 in HTLV-I-infected T cells may contribute to HTLV-I-induced tumorigenesis.
Thus, Tax may induce G1- to S-phase progression in lymphocytes by directly interacting with the cell cycle machinery and by influencing the transcription of cell cycle proteins and transcription factors. Most recently, Tax has also been shown to bind to a mitotic checkpoint protein, MAD1 (141). This suggest that Tax may also interfere with the G2-M phase of the cell cycle, and the specific interaction with MAD1 may explain the ability of Tax to induce multinucleated cells (141).
PROGRAMMED CELL DEATH IN HTLV-I-INFECTED T CELLS
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One mechanism used to control cell growth is programmed cell death
(apoptosis). T cells may undergo apoptosis by at least two separate
mechanisms: (i) withdrawal of growth factors and (ii)
activation-induced cell death (AICD). Withdrawal of growth factors, for
example IL-2, is antigen independent and can be inhibited by the
antiapoptotic proteins Bcl-xL and Bcl-2. In contrast, AICD is antigen dependent, is mediated by CD95 (Fas) or TNF-, and is only
partially inhibited by Bcl-xL or Bcl-2 (298).
The CD95-CD95L interaction plays a crucial role in peripheral AICD, as
demonstrated by experiments with gld mice (deficient in
CD95L) and lpr mice (deficient in CD95), both of which
develop a lymphoproliferative disease (219). Since HTLV-I
can induce a T-cell leukemia/lymphoma and HTLV-I-infected T-cell clones
proliferate spontaneously in the absence of exogenous growth factors
(124), an HTLV-I-mediated interference with normal T-cell
apoptosis might explain the tumorigenic ability of the virus. Indeed,
proteins encoded by EBV (108), adenovirus (243),
and Sindbis virus (177) have been shown to inhibit apoptosis.
Nevertheless, the effect of HTLV-I infection on T-cell survival is controversial. Copeland et al. (48) examined the sensitivity of HTLV-I-infected T-cell lines to anti-CD95 antibody-mediated apoptosis. Despite expression of high levels of CD95, the HTLV-I-infected cell lines showed reduced susceptibility to anti-CD95-induced apoptosis (at antibody concentrations between 1 and 100 ng/ml). The resistance could be transferred to susceptible Jurkat T cells by transfection of a Tax-expressing vector or by treatment with soluble Tax, suggesting that Tax conferred resistance to CD95-CD95L-mediated apoptosis. Brauweiler et al. (28) also found that HTLV-I-infected T-cell lines (SLB, MT-2, MT-4, and HuT-102) were more resistant to apoptosis-inducing stimuli, such as anti-CD95 antibodies (250 ng/ml), taxol, or UV irradiation. Importantly, Tax repressed bax gene expression, and this was mediated by a 27-bp sequence in the bax promoter containing a putative basic helix-loop-helix binding site. Bax is known to promote apoptosis by inhibiting Bcl-xL and Bcl-2, suggesting that Tax-mediated repression of bax may provide a molecular mechanism for the antiapoptotic effect of Tax. In addition, HTLV-I-infected T cells secrete thioredoxin, a small protein regulating the reduction-oxidation status in the cell. Thioredoxin has been reported to protect against oxidative stress-induced apoptosis (reviewed in reference 220).
Several reports have demonstrated that HTLV-I-infected T cells can be induced to undergo apoptosis. Fresh mononuclear cells from ATL patients are activated (CD25+) and sensitive to CD95-mediated apoptosis (55), and IL-2-dependent HTLV-I-infected T-cell lines are susceptible to anti-CD95-induced (54) and activation (CD2)-induced apoptosis (103). These apparently conflicting results may be due in part to differences in anti-CD95 antibodies and the concentrations used. Thus, Debatin et al. (54) used 10- to 100-fold-higher concentrations of anti-CD95 antibodies than did Copeland et al. (48) and Brauweiler et al. (28). Moreover, Debatin et al. (55) examined the feasibility of inducing apoptosis in freshly obtained peripheral blood lymphocytes from ATL patients but did not evaluate whether HTLV-I-infected T cells were more or less susceptible than uninfected T cells. In addition to anti-CD95, adriamycin appears to induce apoptosis in HTLV-I-infected T cells by a p53-independent pathway (85).
While these reports demonstrated the feasibility of inducing apoptosis
in HTLV-I-infected T cells by exogenous stimuli, other observations
have suggested that Tax itself may induce apoptosis. Chlichlia et al.
(42, 43) expressed a fusion protein of Tax either N-terminal
or C-terminal to the hormone binding domain of the estrogen receptor.
Addition of estrogen or hydroxytamoxifen induced Tax transactivation
and upregulation of CD28, CD69, and CD5 but not CD25, which required
additional stimulation through the TCR-CD3 complex (43).
This is surprising, since Tax has been shown to upregulate CD25
(8, 15, 50, 132, 252, 268) and increased expression of CD25
is even detected on HTLV-I-infected T-cell clones with a modest
expression of Tax (124, 247). A potential concern,
therefore, is whether the hormone-mediated induction of Tax had
additional side effects. Importantly, Chlichlia et al. (42,
43) found that induction of Tax promoted apoptosis in T cells
through a pathway that critically required the protease function of the
IL-1-converting enzyme (42). A similar conclusion was
reached by Chen et al. (41) using a
Cd2+-inducible Tax-system (JPX-9). Although Tax induced
CD95 ligand expression (41, 42) and the CD95-CD95 ligand
interaction is known to activate IL-1-converting enzyme-proteases,
blocking experiments failed to implicate this pathway in Tax-mediated
induction of apoptosis (42). In contrast to these
observations, a tetracycline repressor-based Tax expression system
failed to detect apoptosis in lymphocytes expressing Tax
(254).
Tax can induce oncogenic transformation in Rat-1 cells, a cell line derived from rat fibroblasts (285). Nevertheless, in contrast to wild-type Rat-1 cells, Tax-transformed Rat-1 cells underwent apoptosis within 7 days of incubation in serum-free medium, and this was inhibited by overexpression of Bcl-2 (313). This suggests that the expression of Tax makes Rat-1 cells growth factor dependent and susceptible to withdrawal apoptosis. Although the level of Tax expression may be critical for its biologic activities, comparative analysis of the apoptosis-inducing properties of Tax, c-Myc, and c-Fos suggested that Tax possesses relatively low apoptosis-inducing activity (80).
In conclusion, the outcome of HTLV-I infection on T-cell survival is controversial. The ability of Tax to prevent apoptosis of infected T cells is appealing, since Tax may also transform cells and since data from transgenic mice demonstrate that splenic T cells are more resistant to apoptosis induced by anti-CD95 antibodies (154). It is interesting, though, that the adenovirus E1A protein may transform cells and induce apoptosis, which is inhibited by the adenovirus E1B 19-kDa protein (243). If a similar mechanism operates in HTLV-I-infected T cells, it appears to require interaction with a cellular protein in order to explain the conflicting results obtained with Tax-transfected cells (28, 42, 43, 48). Moreover, as mentioned above, it is possible that the concentration of Tax determines the T-cell phenotype.
IMMORTALIZATION AND TRANSFORMATION OF T CELLS BY HTLV-I
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Peripheral or cord blood T cells can be immortalized and
eventually transformed following coculture with HTLV-I-producing T
cells. Here, immortalization means the ability of the T cells to grow
continuously. This may require the presence of exogenous growth factors
(usually IL-2) as in the case of CTLL-2 cells. If, however, exogenous
growth factors are not required, the T cells are transformed, as in the
case of Jurkat cells. The distinction between immortalization and
transformation is important when analyzing the impact of viral
infection on T-cell activation (Table 3).
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The initial stages of HTLV-I-induced T-cell activation can be studied by analyzing in vivo HTLV-I-infected T-cell clones derived by limiting-dilution single-cell cloning of peripheral blood T cells from patients with HAM/TSP (124). T-cell clones are maintained in culture by periodic restimulation with irradiated feeder cells and antigen or mitogen. Whereas uninfected T-cell clones do not incorporate significant amounts of [3H]thymidine 1 week after restimulation, productively infected T-cell clones strikingly incorporate [3H]thymidine in the absence of exogenous growth factors, a phenomenon termed spontaneous clonal proliferation (Fig. 5). This reflects an HTLV-I-induced prolonged state of T-cell activation (124, 206, 239, 309, 322). Nevertheless, HTLV-I-infected T-cell clones are not immortalized, since they do not grow continuously without restimulation with irradiated feeder cells and phytohemagglutinin. Despite their ability to enter S phase 7 to 12 days after restimulation in the absence of exogenous IL-2 (124), the HTLV-I-infected T-cell clones need exogenous IL-2 for growth beyond 12 days and thus are not transformed. It is interesting that HTLV-I-infected T-cell clones are not immortalized, since they are capable of immortalizing peripheral blood lymphocytes in vitro, although with variable efficiency (247).
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The in vitro immortalization process occurs in defined stages. Initially, T-cell growth may decrease and reach a crisis stage which, at about 4 weeks following infection (96), will result in either cell death or increased cell growth. HTLV-I-infected T cells surviving the crisis display upregulated expression of CD25 and MHC class II but remain IL-2 dependent. The initial proliferative phase is characterized by polyclonal proviral integration and transient expression of IL-2 mRNA and IL-2 activity, which is undetectable at later time points (153). At approximately 100 days after infection, proviral integration is oligoclonal, with upregulation of CD25 surface expression but not of IL-2 mRNA. In contrast to IL-2 mRNA, viral tax-rex mRNA is scarcely expressed in the initial phase but is expressed abundantly at later time points (153).
The immortalization is caused by Tax. By inserting the pX region of HTLV-I into transformation-defective but replication competent herpesvirus saimiri, Grassmann et al. (97) demonstrated that the pX region was sufficient for immortalizing human thymocytes and cord blood lymphocytes. Although it cannot be excluded that proteins encoded by herpesvirus saimiri influence the function of HTLV-I proteins, subsequent analyses deleting or inserting nucleotides to generate constructs deficient in the expression of Tax or Rex, or both, have shown that Tax is both necessary and sufficient for immortalizing CD4+ cord blood lymphocytes in this system (96).
An interpretation of the requirements for immortalization and transformation from a cell cycle perspective is shown in Fig. 4. In normal T cells, TCR-mediated activation brings T cells into the G1 phase of the cell cycle, which is associated with activation of tyrosine and serine/threonine protein kinases, Ca2+ flux, and subsequent activation of transcription factors. In addition cyclin D2, D3, CDK4, and CDK6 are synthesized prior to IL-2R signaling (189, 209), which, however, is required to bring T cells beyond the G1 restriction point (36). Phosphorylation of pRb has been proposed to correspond to the restriction point (324), and IL-2R signaling allows pRb phosphorylation by eliminating a critical regulator of the restriction point, the CDK inhibitor p27KIP1 (47, 72, 150, 165, 226, 249).
Tax-immortalized but nontransformed T cells are dependent upon IL-2; hence, they cannot pass the G1 restriction point in the absence of exogenous growth factors. This indicates that overexpression of Tax alone does not induce S-phase progression but that additional events are required. Tax-immortalized T cells are able to enter G1 and, more importantly, do not exit the cell cycle by apoptosis in the presence of appropriate growth factors. The ability of Tax to activate pathways and transcription factors known to be activated in G1 during normal T-cell activation may thus be responsible for the G1 progression (immortalized phenotype).
The transformation of T cells may require the concerted action of
several viral and cellular proteins. Tax may transcriptionally repress
and inactivate the tumor suppressor p53 (39, 237, 293) and
may repress the DNA repair enzyme -polymerase (140), thus enhancing the accumulation of gene mutations. The transformation process, however, is expected to compensate for an IL-2R signal and
hence to phosphorylate pRb and promote S-phase entry in the absence of
exogenous growth factors. Constitutive activation of IL-2R-associated
STAT3 and STAT5 has been demonstrated in HTLV-I-transformed T cells
(202), but STAT5 does not regulate E2F (29) and
thus does not induce pRb phosphorylation and S-phase entry. Recent evidence, however, suggests that Tax expression may promote pRb phosphorylation and the G1/S-phase transition
(254). However, it is unclear whether this is the function
of Tax alone, since control cells immortalized by Tax remained IL-2
dependent. IL-2 induces CREB/ATF1 activity late in G1 in a
cAMP-independent but rapamycin-dependent manner (71). This
activity may be compensated for by Tax expression, since Tax interacts
with CREB/ATF1 and thereby increases its transcription activity. This
interaction is essential for the ability of Tax to transform rat
fibroblasts (272) and to clonally expand CD4+ T
cells (6). Tax-mediated activation of cellular CREs may be
important in T-cell transformation. The mechanism of CREB
phosphorylation in HTLV-I-transformed T cells then becomes important,
since Tax transactivation of cellular CREs is dependent on
phosphorylated CREB (164).
T cells approaching the G1 restriction point may either commit to the cell cycle (if p27KIP1 is downregulated, pRb is hyperphosphorylated, and cyclin E-CDK2 is activated) or undergo apoptosis (if these conditions are not met) (186). Thus, it may be hypothesized that HTLV-I-immortalized T cells may undergo apoptosis in the absence of exogenous IL-2 because they do not approach the G1 restriction point in an appropriate way; i.e., they have not downregulated p27KIP1, which would allow activation of the pRb kinases (cyclin D-CDK4, cyclin D-CDK6, and cyclin E-CDK2). Hence, transformation is an ability to escape apoptosis in late G1, in the absence of an exogenous growth factor. Transduction in early G1 of either p16INK4a or the human papillomavirus E7 protein prevents pRb phosphorylation, further G1 progression, and subsequent activation-induced cell death (186). Interpreted in this way, the ability of Tax to inhibit p16INK4a may activate the cyclin D-CDK complexes and promote cell cycle progression to the restriction point. This may be a critical element in immortalization and perhaps in transformation. In contrast, if the T cell is not ready to enter S phase, forced cell cycle progression may provoke apoptosis. It is conceivable that the apparently contradictory results obtained by analyzing apoptosis in Tax-expressing cells, as discussed above, can be explained by different outcomes of Tax-p16INK4a interaction.
In addition to the G1-S-phase deregulation, the ability of Tax to disturb the mitotic checkpoint protein MAD1 may contribute to the transformation process. Indeed, p53 induces MAD1, and thus Tax may target both G1-S and M checkpoints via p53 (141).
ACTIVATION OF THE CELLULAR IMMUNE SYSTEM BY HTLV-I-INFECTED
T CELLS
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An important consequence of HTLV-I-mediated activation of the host T cell is its ability to further amplify the immune system activation to uninfected, resting T cells in an antigen-nonspecific manner and to antiviral T cells in an antigen-specific manner. Consequently, HTLV-I-infected individuals express several markers of immune system activation (reviewed in reference 49). This amplification of immune system activation may be important for both the spread of the virus and progression to disease.
Activation of Non-Virus-Specific T Cells
Wainberg et al. (300) were the first to detect the T-cell-activating properties of purified HTLV-I. HTLV-I particles were purified from the culture supernatant of an HTLV-I-producing cell line, C10/MJ2, by initial low-speed centrifugation followed by 143,000 × g for 2 h. Subsequently, virus particles were banded by overnight centrifugation through 22 to 53% sucrose gradients and detected by the presence of reverse transcriptase activity. This virus preparation had mitogenic activity when added to mononuclear cells, as assessed by [3H]thymidine incorporation and direct cell counting, but the mechanism was not further explored (300).
Extending this observation, Gazzolo and Duc Dodon (65, 87)
demonstrated that an HTLV-I preparation made by ultracentrifugation (32,000 × g) of culture medium from any of three
different HTLV-I-infected and virus-producing cell lines, C91/PL,
HuT-102, and MT-2, induced T-cell activation mediated by autocrine IL-2
production. In contrast, the pelleted fraction from a Tax-producing but
non-virus-producing cell line, C8166/45, failed to induce T-cell
activation. Preincubation with 10 to 20 µg of anti-Env antibody
(0.5) per ml inhibited the mitogenic activity of a purified virion
preparation made from cell-free C91/PL supernatant run through a
Sepharose CL-4B chromatography column (37). Pooled
fractions, with A260/A280
absorbance greater than 2, were defined as purified HTLV-I. This
purification method preserves envelope glycosylation (198),
which may be important, since pretreatment of C91/PL cells with an
N-linked glycosylation inhibitor, tunicamycin, reduces the mitogenic
activity of the preparation (37). This does not, however,
specifically implicate Env, since tunicamycin also prevents appropriate
glycosylation of other cell surface proteins. Despite the partial
inhibition by 0.5 of the mitogenic activity of the purified virion
fractions, C8166/45 T cells infected by a vaccinia virus construct
expressing recombinant HTLV-I envelope proteins were unable to induce
resting T cells to proliferate (37). Thus, Env proteins
expressed on the virions were found to be mitogenic, in contrast to Env
proteins expressed on the cell surface.
The pathway activated by the viral preparation was inhibited by
antibodies to CD2 (64). The CD2 pathway was initially
described as an alternative T-cell activation pathway (201).
The ligand for CD2 is CD58 (LFA-3) (262, 301). Its
interaction with CD2 is of very low affinity and has an extremely high
dissociation rate (297), which may prevent CD2-CD58
interaction among resting T cells. Nevertheless, upregulated CD58
expression may facilitate clustering. In addition, an isoform of CD58
is glycosylphosphatidylinositol anchored (67), which allows
extra lateral mobility in the membrane. When present on the APC, CD58
can efficiently enhance TCR signaling via CD2 interaction (23-25,
125, 210, 211). The CD2-mediated activation of T cells is
dependent on the intracytoplasmic tail of CD2 (24) and on
CD3, which mediates CD2-induced T-cell activation (125,
211). Thus, the ability of anti-CD2 antibodies to prevent T-cell
activation induced by an HTLV-I preparation (64) implicates CD2 signal transduction in HTLV-I-induced activation of resting T cells.
The hypothesis that HTLV-I particles are intrinsically mitogenic has
been contested by others (152, 309). Using sucrose density
gradient purification, Kimata et al. did not detect mitogenic activity
in purified fractions of MT-2 cell supernatant, although these
fractions were positive for both p19 Gag by enzyme-linked immunosorbant
assay (ELISA) and gp46 Env by Western blot analysis. In addition, none
of nine different antibodies to Env, including the 0.5 antibody,
inhibited the activation of resting T cells mediated by HTLV-I-infected
T cells (152). Similarly, Wucherpfennig et al.
(309) were unable to inhibit the THTLV-I-T-cell
activation by antibodies to Env. Hence, HTLV-I Env proteins expressed
on the surface of T cells are not required for activation of resting T cells.
It is not settled how the CD2 pathway is activated by the HTLV-I preparation (33). It has been demonstrated that cellular proteins are associated with HIV particles (13); thus, CD58 associated with HTLV-I particles following budding through the cell membrane might permit cross-linking of CD2 by free virus. Alternatively, CD58 associated with membranes contaminating the viral preparation may lead to activation of the resting T cells. Indeed, cell membrane fragments from activated T cells and activated T cells fixed by paraformaldehyde can induce [3H]thymidine incorporation in resting T cells. This T-cell-T-cell activation is blocked by antibodies to CD58 and intercellular cell adhesion molecule 1 (ICAM-1) (CD54) (30). Importantly, Kimata and Ratner (153) found that paraformaldehyde fixation still allowed HTLV-I-producing T cells to activate resting peripheral blood T cells. Moreover, Wucherpfennig et al. (309) found that not only anti-CD2 antibodies but also anti-CD58 antibodies inhibited THTLV-I-T-cell activation and the mitogenic activity of HTLV-I virions. This strongly suggests that HTLV-I-induced activation of resting T cells is mediated by CD58-CD2 interaction.
Further characterization of the THTLV-I-T-cell activation demonstrated its partial dependence on the interaction between CD11a/CD18 (LFA-1) and CD54. Although anti-CD54 antibodies had only a marginal blocking effect alone, they enhanced the inhibition achieved by anti-CD58 antibodies. Similarly, a cooperative inhibitory effect was observed between antibodies to CD11a and CD58 (309). Kimata et al. (152) also found that antibodies to CD58 and CD2 blocked the THTLV-I-T-cell activation by using paraformaldehyde-fixed MT-2 cells as stimulator cells and peripheral blood lymphocytes as responder cells. However, they were unable to inhibit the THTLV-I-T cell activation by anti-CD11a or anti-CD54 alone. Combinations of these antibodies and anti-CD58 or anti-CD2 were not examined. However, antibodies to a number of other T-cell surface molecules, including CD80, CD28, CD4, CD8, MHC class I, and MHC class II (anti-HLA-DR, L243, and anti-HLA-DQ, S3/4), and serum with high-titer antibodies to Env and Gag had no significant blocking effect compared to control ascites (309).
Imai et al. (128) examined the expression of 19 different cell adhesion molecules in 14 HTLV-I-infected and 6 uninfected T-cell lines. Except for one HTLV-I-infected T-cell line (MT-1), the mRNA and surface protein expression of CD58 was consistently enhanced in HTLV-I-infected T cells. In addition, the surface expression of CD54 was found to be increased in HTLV-I-transformed T cells (81) and in HTLV-I-infected T-cell clones (256), probably because of Tax-mediated transactivation of the CD54 promoter (232). These observations provide a possible explanation for the ability of HTLV-I-infected T cells to adhere to and activate resting T cells via the CD2 signaling pathway.
Consistent with an IL-2 autocrine mechanism of activation
(87), anti-Tac antibodies to the IL-2R (309)
or anti-IL-2 antibodies (152) inhibited
THTLV-I-T-cell activation. Moreover, Kimata et al.
(152) were able to detect IL-2 mRNA induction in responding Jurkat T cells, and this was blocked by antibodies to CD58. These findings suggest that CD58 expressed on HTLV-I-infected T cells interacts with CD2 on the responding T cells, thereby inducing IL-2
production and IL-2R expression and subsequent IL-2 autocrine T-cell
proliferation. Mononuclear cells from patients with HAM/TSP express
activation markers in vivo and incorporate [3H]thymidine
in the absence of exogenous growth factors when cultured in vitro
(133, 139), a phenomenon termed spontaneous proliferation. The term "spontaneous" does not imply that the mononuclear cells are transformed, since they do not incorporate
[3H]thymidine immediately after being placed in culture,
nor does it imply that these cells will grow in the absence of
exogenous growth factors for a prolonged period. Instead
"spontaneous" refers to the incorporation of
[3H]thymidine on days 3 to 9 in the absence of exogenous
growth factors, which is not seen in mononuclear cells from normal
individuals. Wucherpfennig et al. (309) demonstrated that
antibodies to the adhesion molecules CD11a, CD54, and CD58 and to the
IL-2R chain (CD25) inhibited the spontaneous proliferation,
corroborating the significance of the CD58-CD2 interaction. Since the
THTLV-I-T-cell interaction is antigen nonspecific, it may
potentially occur between any preactivated and resting T cells where
T-cell-T-cell interaction is established. This may explain why the
number of activated T cells expressing MHC class II and IL-2R far
exceeds the number of HTLV-I-infected T cells in many patients with
HAM/TSP (139).
Interestingly, anti-MHC class I (W6/32) and
anti-2-microglobulin antibodies were shown to inhibit
the spontaneous proliferation and HTLV-I expression in peripheral blood
mononuclear cells (196). The mechanism of this inhibition is
unknown but may involve negative signaling mediated by MHC class I
cross-linking. Spontaneous proliferation was not affected by CD8
depletion (196), indicating that it does not reflect a
CD8+-T-cell response to viral epitopes expressed by
HTLV-I-infected CD4+ T cells.
Guyot et al. (102) examined the consequence of CD2-mediated activation of HTLV-I-infected T cells for viral transcription. Antibodies to CD2 but not to CD3 induced a 1.5- to 5.7-fold increase in the level of p24 capsid protein in cell culture supernatant concomitant with a 2- to 4-fold increase in the levels of all species of viral mRNA. Moreover, Jurkat T cells cotransfected with a Tax-expressing plasmid and a CAT reporter gene construct under the control of the HTLV-I promoter demonstrated an 11-fold increase in CAT activity following CD2 stimulation. Thus, by inference, the THTLV-I-T-cell interaction, leading to activation of resting T cells and autocrine IL-2 production, may result in upregulation of CD58 on resting T cells and a reverse interaction involving CD2 activation of the HTLV-I-infected T cells. This would then lead to enhanced viral production and possibly to infection of more T cells. Whereas antibody-mediated activation of the CD2 pathway may result in apoptosis in HTLV-I-infected T cells (103, 305), it is unclear whether this occurs after CD2-CD58 interaction.
The CD58-CD2 interaction has been established as an important costimulatory pathway in THTLV-I-T-cell interaction. In contrast, CD80/CD86-CD28 interaction was found to be important in T-cell-T-cell activation by some investigators (169, 283) but not by others (122), who demonstrated that the combined addition of antibodies to CD80 and CD86 was able to inhibit the costimulatory activity of CD80- and CD86-transfected CHO cells but not the THTLV-I-T-cell interaction. Moreover, in contrast to EBV-transformed B cells, CD86 expressed on T cells was hypoglycosylated and had significantly reduced binding affinity for CTLA4 and no detectable binding to CD28 (122), indicating the presence of cell-type-specific posttranslational modifications of CD86. Although CTLA4 may mediate a negative signal (289, 304), CD86-CTLA4 interaction did not prevent the T-cell-T-cell activation, probably because of the reduced binding affinity and the CD2-CD58 stimulatory signals. However, this finding raises the interesting possibility that CD86 on tumorigenic T cells mediates a negative signal via CTLA4 to effector cells, preventing the elimination of the tumor cells (100).
In addition to membrane-associated molecules, HTLV-I-infected T cells
may induce a number of cytokines, including granulocyte-macrophage colony-stimulating factor, IL-1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-15, TGF-, TNF-, lymphotoxin, and IFN- (reviewed in reference 33), although a single HTLV-I-infected
cell may not produce all of them. By using various cell types and
conditions, different cytokine profiles may be produced. However, IL-6
appears to be frequently upregulated, even in nontransformed T cells, by a mechanism involving Tax-mediated transactivation of the IL-6 promoter (167, 168, 214, 224, 247, 251, 316). The
significance of HTLV-I-induced cytokines is unclear, although they are
likely to influence immunoregulation.
In summary, the CD2-CD58 interaction is critical for the activation of uninfected T cells by HTLV-I-infected T cells. This interaction may potentially also be initiated by virus particles which have incorporated CD58 into the envelope during the budding process through the T-cell membrane. In addition, other adhesion molecules (e.g., CD54-CD11a/CD18) and cytokines (e.g., IL-2 and IL-6) are likely to influence the activation of the uninfected T cells.
Activation of Virus-Specific CD8+ T Cells
Infection by a virus usually elicits an antiviral CD8+
CTL response, which recognizes viral peptide fragments on the surface of the infected cell. Intracellular viral proteins are degraded by
proteases in the cytosol, generating peptides of variable length. Peptides of 8 to 10 residues are preferentially transported into the
endoplasmic reticulum (ER) by an ATP-dependent transporter enzyme, TAP.
In the ER, the peptides bind in the groove between the two -helices
of MHC class I, stabilizing the interaction between MHC class I heavy
chain and 2-microglobulin. The complex between MHC class
I and the viral peptide is transported to the Golgi apparatus, where
further posttranslational modifications occur, and the MHC class
I-viral peptide complex is subsequently expressed on the cell surface.
Here it may indicate to the immune system that the cell is infected and
thereby may induce the education of antigen-specific precursor CTLs.
Importantly, the binding of viral peptide to the MHC class I molecule is restricted in several ways. First, the digestion of the protein in the cytosol must generate 8 to 10 residue peptides that are preferentially transported to the ER and form stable MHC class I-peptide complexes. Second, the MHC class I molecules contain "pockets" with preferences for certain amino acid anchor residues in the peptide (69). Algorithms to predict potential MHC binding peptides from a protein exist, although this does not ensure that the peptide is naturally processed and presented.
Many viruses, especially herpesviruses, have evolved proteins that interfere with the presentation of viral proteins on the cell surface, thereby preventing a strong antiviral CTL response. For example, EBV-infected B cells may restrict viral gene expression to the nuclear antigen, EBNA1, which is poorly processed and therefore not presented on the cell surface (40, 151, 178, 218). Herpes simplex virus type 1 encodes a 9-kDa protein, known as infected-cell polypeptide 47, which inhibits peptide translocation to the ER and thus inhibits MHC class I assembly (5, 76, 112, 290, 320). Infection by cytomegalovirus downregulates MHC class I expression on the cell surface (17, 19, 56, 302, 317) by expression of various viral proteins: the pp65 matrix protein inhibits the presentation of the otherwise abundantly expressed immediate-early gene product p72 (93); the US6 protein inhibits peptide transport into the ER lumen (4, 109, 110); the US11 and U2 proteins dislocate MHC class I molecules from the ER back into the cytosol (144, 306, 307); and the U3 protein results in retention of the MHC class I complex in the ER (3). The adenovirus E3 protein binds to MHC class I and results in its retention in the ER (12, 34, 60, 135, 275, 313), and the HIV protein Nef is implicated in downregulation of MHC class I on HIV-infected T cells (259). Similar mechanisms have not been detected in HTLV-I-infected T cells; rather, infection of glial cells by HTLV-I induced the expression of MHC class I by Tax-mediated transactivation of the MHC class I gene (253).
MHC class I-restricted virus-specific CD8+ T cells can be generated from HTLV-I-infected individuals and may kill cultured tumor cells infected by HTLV-I (148, 206). Indeed, analysis of the CTL response to HTLV-I may be a very sensitive measure of previous viral exposure. In tests of coded peripheral blood lymphocyte samples from HTLV-I-seronegative and PCR-negative individuals previously exposed to HTLV-I, Nishimura et al. (225) found that 7 of 19 had detectable CD8+-T-cell response to Env and Tax proteins, as opposed to 0 of 16 matched controls from individuals without risk factors.
The CD8+-T-cell response to HTLV-I is oligoclonal in
patients with HAM/TSP, although the TCR-V usage differs between
individual patients (82, 99, 117). Jacobson et al. analyzed
the HTLV-I-specific CD8+-T-cell immune response by using
EBV-transformed B cells infected with vaccinia virus expressing HTLV-I
recombinants as target cells (138). The response was
directed primarily against Tax, with a minor response against Env and
Gag. The immunodominant epitope of Tax presented by HLA-A2 was mapped
to amino acids 11 to 19 (147, 157, 294). Surprisingly, the
response to Tax could be demonstrated by using freshly isolated
CD8+ T cells, indicating a high precursor frequency of
virus-specific CD8+ T cells (138). In patients
with HAM/TSP, the precursor frequencies of antiviral cytotoxic
CD8+ T cells were higher than 1/400 in peripheral blood
lymphocytes and were between 1/125 and 1/488 in cerebrospinal fluid
cells (136). Indeed, the real number of virus-specific
CD8+ T cells is likely to be much greater (35,
217). The vaccinia virus approach has the advantage that it may
detect T-cell responses to all the processed and presented peptides as
long as sufficient expression of the recombinant protein allows for
adequate loading of the MHC class I molecules. A comparison of the
CD8+-T-cell response to target cells, either infected with
the vaccinia virus-Tax construct or pulsed with synthetic peptides,
demonstrated that the major response was directed against Tax 11-19 in
HLA-A2 expressing patients and against Tax 186-195 in HLA-B14
expressing patients (68). Importantly, the frequencies of
Tax-reactive CD8+ T cells in HTLV-I-infected asymptomatic
carriers were at least 10-fold lower, 1/2,900 to 1/3,620, and were as
low as 1/20,000 or undetectable in some individuals (68).
Taken together, these data demonstrate a high frequency of Tax-specific
CD8+ T cells in some healthy HTLV-I-infected carriers but a
significantly higher frequency in patients with HAM/TSP.
Studies by Daenke et al., however (51), did not detect a clear difference in the frequency between peripheral blood Tax-specific CD8+ T cells in HAM/TSP patients and healthy HTLV-I-infected carriers. These investigators used target cells pulsed with 15-residue peptides (overlapping by 5 amino acids) spanning Tax and Rex. Since the size of these peptides would be expected to preclude binding in the groove of MHC class I, they may be degraded in the culture medium or may be taken up by the target cell for further processing and presentation. The frequencies of Tax-specific CD8+ T cells in peripheral blood from asymptomatic HTLV-I-infected carriers were on the order of 1/1,400 to 1/3,200 (mean, 1/2,438) (51), comparable to those previously reported (68). However, the frequencies of Tax-specific CD8+ T cells from HAM/TSP patients were more variable (between 1/223 and 1/4,176; mean, 1/906), overlapping with the CD8+-T-cell frequencies of some asymptomatic HTLV-I carriers (51). Thus, while the frequency of virus-specific CD8+ T cells in some HAM/TSP patients is higher than in asymptomatic HTLV-I-infected carriers, it remains to be determined whether this is important for the development of disease.
Using a novel technology, Greten et al. (101) directly examined the frequency of Tax 11-19-specific CD8+ T cells in peripheral blood and cerebrospinal fluid of HAM/TSP patients by Tax 11-19-loaded soluble HLA-A2-immunoglobulin complexes. This confirmed the presence of a high frequency (14%) of these cells in both peripheral blood and cerebrospinal fluid. In one patient, the frequency of Tax 11-19-reactive CD8+ T cells in the cerebrospinal fluid approached 1/4 (101). A high frequency of Tax 11-19-reactive CD8+ T cells in HLA-A2+ HAM/TSP patients has been confirmed by others by direct visualization with HLA-A2/Tax 11-19 tetramer complexes (21).
Additional epitopes of HTLV-I proteins and their MHC restriction have
been characterized, as shown in Table 4.
Using the TAP-defective cell line 174CEM.T2, Pique et al.
(236) characterized potential HLA-A2 binding peptides from
HTLV-I. They found that the strongest binding peptides originate from
the Tax, Env, and Pol proteins, although they did not address whether
the HLA-A2 binding peptides were naturally processed and presented in
an infected cell. Similarly, Schönbach et al. (257)
examined 64 HTLV-I peptides, which matched the predicted binding motif
for HLA-B*3501. The majority of peptides with high-affinity binding for
HLA-B*3501 originated from the Env protein (Table 4). When the peptides
were tested in HLA-B*3501 transgenic mice for their ability to induce a
CTL response, all except one were classified as medium- to
high-affinity HLA-B*3501 binders, suggesting a rough correlation
between HLA affinity and immunogenicity of the peptides, as previously
reported for HLA-A*0201 (265). However, more important but
unresolved questions are whether these peptides are naturally processed
and presented, inducing an immune response in humans expressing
HLA-B*3501.
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Structural Analysis of CD8+-T-Cell Recognition of a Viral Peptide
Immunohistochemistry on autopsy material from the spinal cords of HAM/TSP patients indicates that CD8+ T cells are the predominant cell type found in the inflammatory lesions (212), although CD4+ T cells are found in very early lesions (134). There are two opposing explanations for the observed high frequency of virus-specific CD8+ T cells in HAM/TSP patients (118): (i) CD8+ T cells may kill HTLV-I-infected glial cells directly or may cause demyelination indirectly by initiating an antigen-specific inflammatory response in the central nervous system, causing nonspecific bystander killing of oligodendrocytes; or, conversely, (ii) virus-specific CD8+ T cells may play only a marginal pathogenic role and their high frequency merely represents an ineffective attempt to control the infection. In the first case, it would be desirable to eliminate or anergize the CD8+ T cells, whereas in the latter case, it would be desirable to strengthen the effector functions of the CD8+ T cells. Despite this dilemma in determining the precise function of the CD8+-T-cell response in HAM/TSP, a detailed knowledge about the viral recognition by the CD8+ T cells is necessary to attempt to rationally interfere with the antigen-specific response.
In HLA-A2-expressing individuals, the majority of the
CD8+-T-cell response is directed toward the Tax
11-19/HLA-A2 complex (68, 136, 138). Crystallization of the
Tax 11-19 peptide (LLFGYPVYV) in the groove of HLA-A2 led to the
prediction of four potential TCR contact residues: P1
(Leu11), P5 (Tyr15), P6 (Pro16),
and P8 (Tyr18) (193). The structure of the
ternary complex TCR/Tax 11-19/HLA-A2 confirmed the importance of P5
(Tyr15), which protrudes into the TCR between the third
variable loop of TCR V and V (Fig.
6) and forms contacts with TCR V1,
V2, V3, and V3 (83). The TCR CDR3 loop extends
across the peptide binding site and contacts the HLA-A2 1 domain, P5
to P8 of the Tax 11-19 peptide, and the HLA-A2 2 domain. The
contact between P7 (Val17) and the TCR was unexpected based
on the initial crystal structure of the Tax 11-19/HLA-A2 binary
complex (193). However, binding of TCR to Tax 11-19/HLA-A2
alters the conformation of this MHC class I-peptide complex, pressing
P6 2.7 Å down and moving P7 4.6 Å up, which is sufficient to contact
the TCR (83). In contrast, P1 was not critical for TCR
contact, as predicted by functional data (123, 157). The TCR
binds in a diagonal manner to the HLA-A2/Tax 11-19 complex and this
may be a general feature, since a separate Tax 11-19-reactive TCR,
which differed in 16 of 17 residues that contacted the MHC-peptide
complex, binds in a similar diagonal mode (63).
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Detailed knowledge of the TCR-peptide-MHC class I interaction allows
modulation of the immune response. Single-amino-acid substitutions in
the peptide antigen may generate altered peptide ligands (APLs)
with altered functional properties. Altering the viral peptide antigen
may, however, generate APLs with poor or no ability to bind either MHC
class I or the TCR. Garboczi et al. (84) evaluated the
ability of the ternary complex to assemble with APLs of Tax 11-19 by
using a native gel band shift assay (84). Whereas Tax
11-19, Tax 11-19 (11L
C), and Tax 11-19 (15YA) allowed assembly
of the ternary complex, Tax 11-19 (14GV), Tax 11-19 (16PQ), and
Tax 11-19 (18YA) did not, although they did bind to HLA-A2.
Analyses of Tax-specific CD8+-T-cell clones with a TCR
identical to that crystallized in the ternary complex with Tax
11-19/HLA-A2 demonstrated that a Tax 11-19 (15YA) substitution
altered the response of the virus-specific CD8+ T cells,
since this peptide did not induce clonal expansion or IL-2 production
although it did induce a cytolytic response (123). Similarly, Tax 11-19 (15YA) induced a split in chemokine secretion, with virtually normal MIP-1 secretion but impaired MIP-1
secretion (84) (Table 5).
Moreover, when Tax 11-19 (15YA) was presented by B cells or T
cells, it induced unresponsiveness (anergy) in the CD8+ T
cells (123). Anergic CD8+ T cells maintained the
ability to lyse target cells (120, 231), to proliferate in
response to IL-2, and to respond to TCR ligation by protein tyrosine
phosphorylation and upregulation of CD40L. The induction of anergy can
be prevented by bystander mononuclear cells (120). It is
possible that novel costimulatory molecules (143), cytokines
secreted by professional APCs, or both, are required during the primary
stimulation in order to prevent CD8+-T-cell anergy
induction. Thus, anergy induction by B-cell presentation of antigen
indicates that the types of APC that can induce a productive immune
response are limited and further suggests that the tissue localization
of an immune response to HTLV-I may perhaps be restricted by the
availability of monocytes or dendritic cells. Since Tax presentation by
CD4+ T cells also induced CD8+-T cell anergy
(120), an important question is whether HTLV-I-infected CD4+ T cells can serve as APCs for educating
CD8+ T cells in vivo. Dendritic cells can be infected by
HTLV-I (191) and would be expected to be much more efficient
APCs. Thus, the APC responsible for educating the large number of
antiviral CD8+ T cells in HAM/TSP remains to be determined.
|
Activation of Virus-Specific CD4+ T Cells
Although antiviral cellular immune responses usually reside in the
CD8+ subset of T cells, virus-specific
CD4+-T-cell responses have also been described. However, a
predominantly CD4+ virus-specific T-cell response may
indicate a defect in the antigen presentation pathway, since cytosolic
viral proteins are presented by MHC class I (230). By using
synthetic peptides from Env gp46, CD4+ CTL lines from two
HAM/TSP patients from different geographical areas demonstrated
responses to the same immunogenic region spanning amino acids 196 to
209 (137). This sequence was also shown to elicit a
proliferative response in immunized mice (163). The CD4+-T-cell response in naive (uninfected) individuals to
HTLV-I Env was directed toward Env gp46 peptides spanning amino acids
76 to 90, 136 to 160, 171 to 185, and 196 to 210 and toward Env gp21 peptides spanning amino acids 366 to 400 and 436 to 485. The gp21 epitopes were restricted by HLA-DRB1*0101 and HLA-DRB1*1502, alleles that are frequently found in HAM/TSP patients from Japan
(315). The CD4+-T-cell response to Env peptides
in HTLV-I seronegative individuals is characterized by heterogeneous
TCR V usage (195), whereas the TCR V usage in
Env-specific CD4+ T cells from HAM/TSP patients has not
been analyzed.
CONCLUSIONS
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HTLV-I infects CD4+ T cells and incorporates into the genome as a provirus. Whereas more than 10% of CD4+ T cells may be infected in vivo, only a small fraction of productively infected T cells cause activation of the immune system. While an activated immune system is needed to eradicate the infection, the spread of the virus is also accelerated under these conditions. The interactions between HTLV-I and the cellular immune system can be divided into viral interference with functions of the infected host T cell and the subsequent interactions between the infected T cell and the cellular immune system.
HTLV-I-mediated activation of the infected host T cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction pathways, cell cycle control, and apoptosis. These properties of Tax recapitulate T-cell activation events during the G1 phase of the cell cycle and may well explain the ability of Tax to immortalize T cells. However, it is not yet clear how HTLV-I induces T-cell transformation. An important function of IL-2 may be to activate CREB/ATF, which are also activated by Tax. Furthermore, recent evidence suggests that Tax may promote the G1/S-phase transition, although this may involve additional proteins. A role for other viral proteins that may constitutively activate the IL-2R pathway in HTLV-I-immortalized T cells has also been suggested. In addition, Tax may abrogate a mitotic checkpoint.
By virtue of their activated state, HTLV-I-infected T cells can nonspecifically activate resting, uninfected T cells via virus-mediated upregulation of adhesion molecules. This may also favor viral dissemination, since transmission of HTLV-I usually requires T-cell-T-cell interaction. Moreover, the induction of a remarkably high frequency of antiviral CD8+ T cells does not appear to eliminate or control the HTLV-I infection. Indeed, individuals with a high frequency of virus-specific CD8+ T cells have a high viral load, indicating a state of chronic immune system stimulation. It is not understood why such a high frequency of antiviral CD8+ T cells (1 in 4 CD8+ T cells may be specific for a single viral epitope) can coexist with such a high frequency of virus-infected CD4+ T cells. Perhaps the circulation of infected CD4+ T cells allows them to escape CD8+-T-cell-mediated killing.
Thus, the complex interaction of HTLV-I with T cells allows the virus to persist in the host by expanding the population of infected T cells and by enhancing the spread of the virus to uninfected resting T cells. The host responds to the infection by a vigorous education of virus-specific CD8+ T cells but fails to eliminate the virus. Our detailed knowledge of the molecular interactions between virus-specific CD8+ T cells and immunodominant viral epitopes holds promise for the development of specific antiviral therapy.
ACKNOWLEDGMENTS
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I thank G. J. Buckle and D. A. Hafler for discussions.
I thank the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the National Multiple Sclerosis Society for supporting part of my work referenced in this review.
FOOTNOTES
* Mailing address: Division of Virology, Department of Medical Microbiology and Immunology, Bartholin Building, Aarhus University, DK-8000 Aarhus, Denmark. Phone: 45 8942 1772. Fax: 45 8619 6128. E-mail: ph{at}microbiology.au.dk.
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