Biomedical subjects

P Höllsberg

Publications and source records attributed to P Höllsberg.

At least 19 recordsLinked to original sources

PubMed2005

Presence of Epstein-Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity.

OBJECTIVE: To assess the presence of Epstein-Barr virus (EBV) and human herpesvirus 6B (HHV-6B) DNA in saliva and plasma from multiple sclerosis (MS) patients enrolled in a randomized, double-blind, placebo-controlled valacyclovir treatment study. METHODS: DNA was prepared following ultracentrifugation of saliva and plasma. EBV and HHV-6B DNAs were determined by real-time polymerase chain reaction. RESULTS: EBV and HHV-6B DNAs were detected in 41% and 65% of saliva samples, respectively. In patients treated with valacyclovir, the percentage of saliva samples with EBV was significantly reduced (9%; P = 0.000017), whereas the frequency of HHV-6B positive samples was unchanged (57%; P = 0.38). Longitudinal studies demonstrated a time-dependent reduction in the frequency of saliva samples containing EBV following valacyclovir treatment. In contrast, plasma contained EBV and HHV-6B DNAs in 17% and 25% of the samples, respectively, and these numbers were not significantly reduced following valacylovir treatment (13% and 16%, respectively), nor were they different from those of healthy controls (6% and 39%, respectively). Patients with high disease activity had a significantly higher frequency of EBV (P = 0.018) and HHV-6B (P = 0.023) positive samples than did patients with low disease activity. The presence of EBV and HHV-6B was strongly correlated in plasma (P < 0.00000001), but not in saliva (P = 0.41). CONCLUSION: MS patients express EBV and HHV-6B in both saliva and plasma, but only the expression of EBV in saliva is significantly reduced following valacyclovir treatment. Although EBV and HHV-6B DNAs can be detected in plasma from healthy individuals, the co-expression of both these viruses in MS patients is highly significant and further associated with clinical activity. The observations of viral DNA in plasma are consistent with an underlying immunologic defect in MS.

Acyclovir↗

PubMed2004

A role of late Epstein-Barr virus infection in multiple sclerosis.

OBJECTIVE: To assess Epstein-Barr virus (EBV) seroconversion in a high multiple sclerosis (MS) prevalence area and to evaluate the recall of diagnosed infectious mononucleosis in MS patients. METHODS: The study was based on information or blood samples, or both, from schoolchildren, young MS patients and matched controls. EBV serology was performed on 1154 blood samples. RESULTS: We demonstrate that more than one third of the population in a high MS prevalence area is seronegative to EBV at puberty. This is in contrast to the virtually complete seroconversion to EBV early in life in individuals from areas with a low prevalence of MS. Furthermore, we demonstrate that recall of diagnosed infectious mononucleosis (IM), but not recall of common childhood diseases, is significantly more frequent among MS patients than healthy controls. All MS patients, including patients without prior immunosuppressive treatment, were EBV seropositive. CONCLUSION: During or after puberty, EBV is transmitted to a major proportion of the population in an MS high-prevalence area. Together with our previous documentation of an association between late infection with EBV and an increased risk of developing MS, these data support a role of EBV infection in MS.

Adolescent↗

PubMed2003

Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis.

An increased frequency of antiviral CD8+ T cells is seen in chronic viral infections. During herpes virus infections the expanded CD8+ T cells are thought to control the reactivation of the latent infection. Because multiple sclerosis (MS), a presumed autoimmune disease of the central nervous system, has been associated with a late Epstein-Barr virus (EBV) infection, we wished to examine whether the CD8+ T cell response to EBV epitopes differed between MS patients and healthy controls. Here we report an increased frequency of CD8+ T cells responding to EBV epitopes from nuclear antigen 3 A (HLA-A2/CLG) and latent membrane protein 2 (HLA-B7/RPP) in MS patients. Noticeably, the altered CD8+ T cell response occurred to some but not all EBV epitopes and did not reach the high level seen during acute infection. The responses towards two immunodominant epitopes from human cytomegalovirus (HCMV) were similar in MS patients and normal controls. Together, our data demonstrate the presence of an increased frequency of CD8+ T cells reacting with two epitopes from EBV in patients with MS. The altered response to only two of the tested EBV epitopes would be consistent with the presence of cross-reactive epitopes.

Adult↗

PubMed2002

A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS.

OBJECTIVE: To evaluate the effect of treatment with the antiherpes drug valacyclovir on MRI-evident lesions in patients with relapsing-remitting MS in a phase 2, randomized, double-blind, placebo-controlled study. BACKGROUND: It has been postulated from virologic studies that herpesvirus infection could play a role in the progression of MS. METHODS: Patients were eligible for the study if they had had two or more MS relapses in the 2-year period before enrollment. Seventy patients with Expanded Disability Status Scale scores of 0 to 5.5 were randomly assigned to receive 1 gram of valacyclovir (n = 36) or placebo (n = 34) three times daily for 24 weeks. Patients underwent MRI every fourth week for 32 weeks: twice during pretreatment, six times during treatment, and once after treatment. Scoring of neurologic disability was performed at the start and end of the treatment period. The primary endpoint was the number of new active MRI-evident lesions over 24 weeks of treatment. Secondary endpoints included other MRI measures and clinical endpoints. RESULTS: The mean number of new active lesions +/- SD per patient during 24 weeks of treatment with valacyclovir was 11.9 +/- 17.6 and that during placebo treatment was 14.5 +/- 21.4. A protocol-planned exploratory analysis stratified patients according to baseline activity; this analysis showed that patients with high levels of disease activity in the valacyclovir treatment group (n = 17) developed fewer new active lesions per scan than did those in the placebo treatment group (n = 11). The median number (Q(1), Q(3) range) of active lesions was 2.0 (1.38, 3.96) in the valacyclovir treatment group and 6.5 (2.63, 9.0) in the placebo treatment group. CONCLUSIONS: Valacyclovir treatment did not reduce the formation of active lesions in patients with relapsing-remitting MS who had two or more relapses during the previous 2-year period. In a subgroup of patients with high levels of disease activity who had more than one active MRI-evident lesion during 4 weeks, valacyclovir treatment was associated with a reduced number of new active MRI-evident lesions and with an increase in the number of scans free of new active lesions. The results of the exploratory subgroup analysis provide support for further studies of antiherpes therapy for patients with MS and high levels of MRI-evident disease activity.

Acyclovir↗

PubMed2002

Contribution of HLA class I allele expression to CD8+ T-cell responses against Epstein-Barr virus.

Most immune responses to viral infections involve CD8+ T cells recognizing viral peptides of typically 9-10 amino acids in the groove of major histocompatibility complex (MHC) class I. Importantly, CD8+ T-cell responses appear to focus on few viral epitopes, a phenomenon termed immunodominance. While the understanding of this phenomenon has been based largely on experimental mice models, it is imperative to evaluate its contribution in humans, as the design of peptide-based vaccines may be influenced by immunodomination. Here, we present evidence that immunodominance can be detected among Epstein-Barr virus (EBV) epitopes associated with two of the most frequent class I alleles in Western Europe, human leucocyte antigen (HLA)-A2 and HLA-B7. CD8+ T-cell responses to HLA-A2-associated EBV epitopes were significantly reduced in individuals coexpressing HLA-B7. The impairment of HLA-A2-associated responses correlated with a dominant response to an HLA-B7 epitope. The data demonstrate a hierarchy in the human cellular immune response to immunodominant EBV epitopes presented by separate HLA class I alleles. This may have implications for EBV vaccine development as well as for the interpretation of isolated analysis of immunodominant responses to EBV.

Alleles↗

PubMed1999

HTLV-I-infected T cells evade the antiproliferative action of IFN-beta.

Human T-cell lymphotropic virus type I (HTLV-I)-infected T-cell clones enter the S-phase of the cell cycle in the absence of exogenous IL-2. The pathway by which HTLV-I activates the host T cell may circumvent normal immunoregulatory mechanisms and thus be important for the pathogenesis of HTLV-I-induced diseases. The early control of viral infections is in part mediated by interferons (IFNs), which possess both antiviral and antiproliferative functions. In order to investigate the antiproliferative effect of IFN-beta on HTLV-I-induced T-cell activation, we generated T-cell clones from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis by single-cell cloning under limiting dilution conditions. Here we demonstrate that HTLV-I-induced T-cell proliferation is resistant to the antiproliferative action of IFN-beta. Moreover, HTLV-I-infected T-cell clones continue to constitutively secrete IFN-gamma in the presence of high doses of IFN-beta. HTLV-I-infected T cells express normal levels of IFNAR1 and are able to respond to IFN-beta by phosphorylation of STAT1 on Tyr701, although they display a relative increase in phosphorylation of the transcriptionally inactive STAT1beta when compared with STAT1alpha. Thus, HTLV-I promotes cell cycle progression in G1 by a mechanism that overcomes inhibitory signals, thereby circumventing an innate immune defense mechanism.

Cell Cycle↗

PubMed1999

Direct analysis of viral-specific CD8+ T cells with soluble HLA-A2/Tax11-19 tetramer complexes in patients with human T cell lymphotropic virus-associated myelopathy.

Human T cell lymphotropic virus-I (HTLV-I)-associated myelopathy is a slowly progressive neurologic disease characterized by inflammatory infiltrates in the central nervous system accompanied by clonal expansion of HTLV-I-reactive CD8+ T-cells. In patients carrying the HLA-A2 allele, the immune response is primarily directed to the Tax11-19 peptide. The frequency, activation state, and TCR usage of HLA-A2/Tax11-19 binding T cells in patients with HTLV-I-associated myelopathy was determined using MHC class I tetramers loaded with the Tax11-19 peptide. Circulating Tax11-19-reactive T cells were found at very high frequencies, approaching 1:10 circulating CD8+ T cells. T cells binding HLA-A2/Tax11-19 consisted of heterogeneous populations expressing different chemokine receptors and the IL-2R beta-chain but not the IL-2R alpha-chain. Additionally, Tax11-19-reactive CD8+ T cells used one predominant TCR Vbeta-chain for the recognition of the HLA-A2/Tax11-19 complex. These data provide direct evidence for high frequencies of circulating Tax11-19-reactive CD8+ T cells in patients with HTLV-I-associated myelopathy.

Adult↗

PubMed1999

Mechanisms of T-cell activation by human T-cell lymphotropic virus type I.

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.

Apoptosis↗

PubMed1997

Expression of a hypoglycosylated form of CD86 (B7-2) on human T cells with altered binding properties to CD28 and CTLA-4.

CD80 (B7-1) and CD86 (B7-2) on APC provide a major costimulatory signal through interactions with CD28 on T cells. Absent from resting human T cells, CD86 is up-regulated early upon T cell activation, whereas CD80 expression appears later. Whereas T cell expression of CD80 has been implicated in costimulation, the functional significance of CD86 expression on T cells is unclear. We now demonstrate that CD86 expressed on human CD4+ T cell clones does not provide a costimulatory signal for other CD4+ T cell clones. Binding studies using CD28-Ig and CTLA-4-Ig fusion proteins demonstrate that CD86 expressed on T cells has significantly reduced binding affinity for CTLA-4 and no detectable binding to CD28. Biochemical analysis demonstrates that post-translational modifications of CD86 in human T cells are different from those of CD86-transfected Chinese hamster ovary cells or EBV-transformed B cells, in that T cells express a hypoglycosylated form of CD86 on the surface membrane. Thus, our results suggest that while CD86 is expressed on a number of different cell types, its costimulatory function and affinity for its ligands may be regulated by cell type-specific post-translational modifications.

Abatacept↗

PubMed1997

Autoantigen recognition by human CD8 T cell clones: enhanced agonist response induced by altered peptide ligands.

Determination of immunodominant epitopes of MHC class I-restricted self-Ags and elucidation of TCR contact residues is of potential importance in providing a means of manipulating the immune response to self-Ags in human autoimmune diseases. A computer algorithm was used to examine the sequences of the two major encephalitogenic proteins of myelin, MBP and PLP, for HLA-A2 binding motifs. Thirty-eight peptides with HLA-A2.1 binding motifs were synthesized and their binding to HLA-A2.1 was measured. A panel of HLA-A2-restricted T cell clones directed against the PLPp80-88 epitope, which exceeded the binding affinity of the other myelin-peptides tested by at least one order of magnitude, was generated. Using a set of analogue peptides with single amino acid substitutions, we detected a distinct pattern of TCR contact residues for each clone. Surprisingly, modification of different presumed TCR contact residues generated superagonist peptides, which are defined as peptides with equal or lower MHC binding affinity to HLA-A2 that induce half-maximal effector responses at 100-fold lower concentrations than the original peptide. These agonist peptides could drive cytotoxic T cell clones to proliferate, secrete cytokines, and clonally expand at concentrations at which the native peptide induced only cytotoxic responses. The proliferation induced by the superagonist peptides gives additional evidence that the clonal expansion of CD8 T cell clones may in part be regulated on the level of Ag recognition by the TCR.

Amino Acid Substitution↗

PubMed1997

Weak peptide agonists reveal functional differences in B7-1 and B7-2 costimulation of human T cell clones.

The influence of costimulation on the T cell response to altered peptide ligands that act as either partial or weak agonists for human CD4+ T cell clones was examined. Using stable Chinese hamster ovary (CHO) cell transfectants expressing DR2 (DRB1*1501) and human B7-1 or B7-2 as APC, presentation of native myelin basic protein (MBP) p85-99 peptide Ag or a partial agonist of MBP p85-99 induced equivalent T cell activation as measured by [3H]TdR incorporation and cytokine secretion. In marked contrast, presentation of cross-reactive peptides of MBP p85-99 that act as weak agonists with B7-1, but not B7-2, costimulation resulted in significant T cell activation as measured by [3H]TdR incorporation and cytokine secretion. These data suggest that decreasing the strength of the signal provided to the TCR allows differences in B7-1 and B7-2 signaling to be observed. Thus, the costimulatory environment during T cell activation may be a mechanism of regulating T cell cross-reactivity in the periphery.

Amino Acid Sequence↗

PubMed1997

Variable immortalizing potential and frequent virus latency in blood-derived T-cell clones infected with human T-cell leukemia virus type I.

Human T-cell leukemia virus type I (HTLV-I)-infected T cells expanded in vitro by single-cell cloning provide a unique system for investigating virus-cell interactions in nonimmortalized T cells. By analysis of clones generated randomly from the blood of virus carriers, we confirm that CD4 T cells are the major reservoir of HTLV-I in vivo and show that most infected cells contain a single integrated provirus. Contrary to the situation in HTLV-I immortalized cell lines, the HTLV-I provirus was found to be transcriptionally silent in a high proportion of randomly generated T-cell clones and could not be reactivated by mitogenic stimulation. The spontaneous proliferation previously documented in HTLV-I-infected T-cell clones was not observed in silently infected cells, and therefore correlates directly with the expression of tax and other viral genes. The only cytokine mRNA found to be significantly elevated in the virus-producing clones was interleukin-6; however, receptor-blocking experiments argue against a role for IL-6 in the virus-induced cell proliferation. We observed a striking variation in the ability of individual HTLV-I-producing clones to immortalize fresh peripheral blood lymphocytes. This ability did not correlate with the levels of viral mRNA expression, gag p24 production, spontaneous proliferation, or tax-transactivation, possibly suggesting a role for host cell factors as determinants of viral infectivity or immortalization. Studies to elucidate the basis of this phenotypic heterogeneity should enhance our understanding of viral spread and pathogenesis.

Blotting, Southern↗

PubMed1997

B7.2 expressed by T cells does not induce CD28-mediated costimulatory activity but retains CTLA4 binding: implications for induction of antitumor immunity to T cell tumors.

The B7 family of costimulatory molecules provides the second signal necessary for activation of T cells. In the absence of the second signal, responding T cells become anergic. Although predominantly expressed on professional APCs, recent evidence shows that the B7 molecules are also expressed on T cells. To study the functions of B7 molecules on T cells, we transfected murine B7.1 (CD80) and B7.2 (CD86) cDNAs into the EL4 T cell thymoma cell line and examined the transfectants for their ability to costimulate T cell proliferation in vitro and to induce antitumor immunity in vivo. Here we show that although EL4-B7.1 cells costimulate T cells and induce tumor regression, EL4-B7.2 transfectants failed to costimulate T cell proliferation or induce tumor regression. To understand the cellular basis for this difference, we examined the binding of EL4-B7.1 and EL4-B7.2 to CTLA4 and CD28. Whereas EL4-B7.1 cells bound both CTLA4-Ig and CD28-Ig, EL4-B7.2 transfectants preferentially bound CTLA4-Ig, but not CD28-Ig. Similar binding data were obtained with freshly isolated murine T cells, which have been shown to constitutively express B7.2. Our data suggest, therefore, that B7.2 expressed on T cells may not costimulate but instead inhibit the T cell response by preferential binding to CTLA4.

Abatacept↗

PubMed1997

Pathogenesis of chronic progressive myelopathy associated with human T-cell lymphotropic virus type I.

Human T-cell lymphotropic virus type I (HTLV-I) induces a chronic demyelinating disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). While only 0.25% of HTLV-I-infected individuals develop HAM/TSP, the mechanisms responsible for the progression of an HTLV-I carrier state to clinical disease are not clear. In particular, no specific sequence differences have been found between HTLV-I recovered from HAM patients and HTLV-I-infected carriers. Since CD4 T cells are the major reservoir of the virus, at least three hypotheses implicating CD4 T cells directly or indirectly have been proposed: 1) The cytotoxic hypothesis predicts that activated and HTLV-I-infected CD4 T cells migrate to the CNS and infect resident cells. Cytotoxic CD8 T cells may then recognize viral antigens on HTLV-I-infected CNS cells causing a cellularly mediated cytotoxic demyelination. 2) The autoimmune hypothesis predicts that either (a) virally reactive T cells crossreact with a CNS antigen, or (b) random infection of CD4 T cells eventually results in the infection of CNS-autoreactive CD4 T cells that, by virtue of the productive HTLV-I infection, become activated, expand and migrate to the CNS, where they encounter their antigen. This results in a specific immune response and demyelination, as is known to occur in experimental autoimmune encephalomyelitis. 3) The bystander damage hypothesis does not implicate a specific response against CNS cells. Instead this hypothesis suggests that the presence of IFN-gamma-secreting HTLV-I-infected CD4 T cells and their recognition by virally specific CD8 T cells in the CNS induce microglia to secrete cytokines, such as TNF-alpha, which may be toxic for the myelin.

Autoantibodies↗

PubMed1996

Induction of anergy in CD8 T cells by B cell presentation of antigen.

Induction of T cell anergy is thought to occur during activation in the absence of adequate costimulation. Here we demonstrate induction of anergy in a CD8 T cell clone by its cognate Ag in the presence of B7-1 and B7-2 costimulation. Primary activation of a CD28+CD8+ T cell clone by either human T cell lymphotrophic virus type I (HTLV-I) Tax11-19 peptide-pulsed EBV-transformed B cells, CD40L-stimulated B cells, or T cells was sufficient to induce complete unresponsiveness to a secondary Ag challenge. This was not caused by lack of B7 costimulation since the APCs expressed B7-1 and B7-2 and failed to induce anergy in an MBP peptide 84-102-reactive CD4 T cell clone. While anergic CD8 T cells did not proliferate, they retained their ability to lyse peptide-pulsed target cells. However, Ag stimulation failed to induce IL-2 mRNA transcription and IL-2 secretion, although immediate early tyrosine phosphorylation was normal and anti-CD3 cross-linking induced identical levels of CD40L expression in anergized and non-anergized CD8 T cells. Secondary Ag stimulation in the presence of exogenous IL-2, however, resulted in normal proliferative response. Moreover, while stimulation of CD8 T cells with PHA and B cells induced anergy, CD8 T cell stimulation with PHA and mononuclear cells failed to do so. In addition, the presence of mononuclear cells during the exposure of CD8 T cells to peptide-pulsed B cells prevented the induction of anergy. Together, our observations demonstrate that at least a subpopulation of CD8 T cells are anergized when costimulation is provided by B cells or T cells.

Antigen-Presenting Cells↗

PubMed1996

Activation of human T cell lymphotropic virus type I-infected T cells is independent of B7 costimulation.

Two distinct signals are required to activate T cells: an Ag-specific signal and a costimulatory signal mediated primarily by B7-1 (CD80) and B7-2 (CD86) through interactions with CD28. Costimulation appears to be critical in regulating autoreactive T cell responses. Here, we demonstrate that, in contrast to the parental uninfected T cell clone, a T cell clone infected by human T cell lymphotropic virus type I (HTLV-I) displays a remarkably enhanced response to Ag in the absence of B7 costimulation. Chinese hamster ovary cells either transfected with DRB1*1501 (t-DR2) alone or cotransfected with DR2 and either B7-1 or B7-2 were fixed, pulsed with myelin basic protein peptide 84-102 (MBPp84-102), and used as APCs. The MBPp84-102-reactive T cell clone Ob1A12.8 required costimulation with either B7-1 or B7-2 molecules, as the response to Ag was reduced by 90% in the absence of B7 costimulation. However, this requirement for B7 costimulation was abrogated after productive infection by HTLV-I. Stimulation of HTLV-I-infected T cells by MBPp84-102/t-DR2 induced the secretion of IL-5 and IFN-gamma, which approached the level induced in the presence of B7 costimulation, whereas IL-4 was induced to one third of its maximal level. Consistently, the secretion of IL-5 and IFN-gamma was not significantly inhibited by anti-B7-1 and B7-2 Abs, whereas IL-4 was inhibited by approximately 50%. In contrast, uninfected T cells required either B7-1 or B7-2 costimulation for significant cytokine secretion, and this response was inhibited by anti-B7-1 and B7-2 Abs. These findings suggest that HTLV-I-infected autoreactive T cells have the potential to induce an autoimmune response in the absence of B7 expression in the target organ. This may be of particular interest in the elucidation of HTLV-I pathogenicity given the association of HTLV-I infection with autoimmune-like diseases.

Animals↗

PubMed1996

Downregulation of IL-10 secretion and enhanced antigen-presenting abilities following HTLV-I infection of T cells.

Human T-cell lymphotropic virus type I (HTLV-I) may infect up to 10% of peripheral blood T cells in patients with HTLV-I myelopathy. To examine the impact of HTLV-I infection on the abilities of T cells to present and respond to peptide antigen, we HTLV-I infected and subcloned a myelin basic protein peptide 84-102 (MBP p84-102)-specific T-cell clone. The HTLV-I-infected subclones displayed spontaneous clonal proliferation, as observed in T-cell clones from HTLV-I myelopathy patients, indicating virally induced T-cell activation. In the presence of soluble peptide antigen, the HTLV-I-infected T cells responded to a 100-fold lower peptide concentration than did the uninfected parental T-cell clone. This response was not mediated by virally induced priming for hyperresponsiveness because peptide-pulsed Epstein-Barr Virus (EBV)-transformed B cells or HLA-DR2/B7-1 or B7-2 transfected Chinese hamster ovary (CHO) cells activated uninfected T cells at least twofold better than HTLV-I-infected T cells. Instead, the HTLV-I-infected T cells were better antigen-presenting cells when compared to activated, uninfected T cells and the enhanced ability to present antigen correlated with a marked upregulation in surface expression of major histocompatibility complex (MHC) class II and LFA-3. The ability of HTLV-I-infected T cells to activate other T cells was not simply caused by their state of activation. In contrast with activated and uninfected parental T cells, HTLV-I-infected T cells had downregulated secretion of the immunosuppressive cytokine IL-10, whereas interferon-gamma secretion was significantly increased. Because IL-10 inhibits human CD8 T-cell proliferation, the enhanced antigen-presenting abilities of HTLV-I-infected T cells and the downregulation of IL-10 may be important contributors to the general immune activation and potentially to the remarkably high frequency of cytotoxic T cells observed in HTLV-I myelopathy patients.

Animals↗

PubMed1996

HTLV-I-induced T-cell activation.

Infection by the human T-cell lymphotropic virus type I (HTLV-I) causes T-cell activation by at least two separate mechanisms. One mechanism involves activation of the T cells harboring the virus and is exemplified by in vivo infected nonimmortalized T-cell clones that display a prolonged state of activation. This HTLV-I-induced T-cell activation is inhibited by rapamycin, a drug that inhibits p70 S6-kinase and blocks cell cycle in G1, but is not inhibited by FK506 or cyclosporin A, both of which inhibit interleukin-2 (IL-2) production. The phenotype of this pathway is consistent with an hyperactive IL-2R pathway or CD28 pathway, indicating that HTLV-I may contribute a costimulatory signal to the infected T cell. As a separate mechanism, HTLV-I-infected T cells can induce activation of uninfected T cells via T-T-cell interaction mediated by the LFA-3-CD2 pathway. This may induce IL-2 production from the uninfected T cells, leading to a more generalized activation of the immune system that potentially could provide a basis for some of the diseases associated with HTLV-I. Moreover, this THTLV-I-T-cell interaction could explain the spontaneous proliferation observed in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

CD2 Antigens↗