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At least 55 records · Page 3Linked to original sources
PubMed2000

Identification of dominant optimal HLA-B60- and HLA-B61-restricted cytotoxic T-lymphocyte (CTL) epitopes: rapid characterization of CTL responses by enzyme-linked immunospot assay.

Human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T-lymphocyte (CTL) responses play a major role in the antiviral immune response, but the relative contribution of CTL responses restricted by different HLA class I molecules is less well defined. HLA-B60 or the related allele B61 is expressed in 10 to 20% of Caucasoid populations and is even more highly prevalent in Asian populations, but yet no CTL epitopes restricted by these alleles have been defined. Here we report the definition of five novel HLA-B60-restricted HIV-1-specific CTL epitopes, using peripheral blood mononuclear cells in enzyme-linked immunospot (Elispot) assays and using CTL clones and lines in cytolytic assays. The dominant HLA-B60-restricted epitope, Nef peptide KEKGGLEGL, was targeted by all eight subjects with B60 and also by both subjects with B61 studied. This study additionally establishes the utility of the Elispot assay as a more rapid and efficient method of defining novel CTL epitopes. This approach will help to define new CTL epitopes that may play an important role in the immune control of HIV-1.

Adult↗
PubMed1986

Expression of CTL-defined, AKR/Gross retrovirus-associated tumor antigens by normal spleen cells: control by Fv-1, H-2, and proviral genes and effect on antiviral CTL generation.

In previous studies we have characterized H-2-restricted cytolytic T lymphocytes (CTL) type specific for Gross cell surface antigen-positive tumor cells induced by AKR/Gross leukemia viruses. The generation of such CTL was shown to be controlled by at least three genetic loci including H-2 and Fv-1. The Fv-1n phenotype was able to negate positive immune response gene effects of the H-2b haplotype. Fv-1n-mediated inhibition appeared to operated by allowing the early expression by normal cells of N-ecotropic leukemia virus-related antigens recognized by the antiviral CTL, perhaps via tolerance induction. In the present study, the expression of CTL-defined viral antigens by normal cells is further considered. Possible gene dosage effects by H-2 as well as Fv-1 and the other virus-related (V) genes, including proviral structural loci, were examined by comparison of a panel of congenic and F1 mice. These experiments indicated that the quantitative level of expression of CTL-defined viral antigens was primarily controlled by the Fv-1 genotype. Gene dosage effects were also observed for the V genes and, in some situations, for H-2. The importance of the early display of viral antigens by normal cells was underscored by the inability of those mice to generate specific antiviral CTL responses. Even strains expressing low levels of viral antigens, such as responder X nonresponder (AKR.H-2b:Fv-1b X AKR.H-2b)F1 mice, failed to respond. These results are discussed with respect to the inability of mice of the AKR background to respond with specific antiviral CTL generation and in light of their high incidence of spontaneous leukemia.

AKR murine leukemia virus↗
PubMed1997

Influence on CD8 of TCR/CD3-generated signals in CTL clones and CTL precursor cells.

Alloreactive CTL clones and naive CTL precursor cells (CTLp) from TCR-transgenic mice were analyzed for their response in total and in TCR-associated kinase activation upon stimulation with the relevant class I allo-APCs. The responses were found to be stronger and more sustained for the CTL clone and CTLp expressing a TCR previously characterized as CD8 coreceptor independent than for the CTL clone and CTLp expressing a TCR characterized as CD8 dependent. Unexpectedly, it was found that also in response to CD3 engagement, total and TCR-associated kinase activation were stronger and more sustained in the CTL clone and CTLp expressing the CD8-independent TCR. In both types of CTL clones, p56(lck) was found associated with the TCR complex, and CD3 components were found associated with CD8 before CD3 engagement. Upon CD3 engagement, ZAP-70 was also found associated with the TCR complex and the kinase activity (p56(lck)) associated with CD8 increased. This increase was more pronounced for the CD8-independent than for the CD8-dependent clone. An increased association of CD3zeta with CD8 was also detected after CD3 engagement for each clone. These data indicate that signals resulting from exclusive CD3 engagement can influence CD8 molecular associations and activate CD8-bound p56(lck). They further suggest that clonal differences exist that influence the efficiency of signaling upon binding of the same CD3 ligand. The observation that this property was shared between independently derived CTL clone and CTLp expressing the same TCR suggests that it may be acquired during repertoire selection.

Animals↗
PubMed1997

Analogues of CTL epitopes with improved MHC class-I binding capacity elicit anti-melanoma CTL recognizing the wild-type epitope.

The MHC class-I binding affinity of an epitope is an important parameter determining the immunogenicity of the peptide-MHC complex. In order to improve the immunogenicity of an epitope derived from melanocyte lineage-specific antigen gp100, we performed amino-acid substitutions within the epitope and assayed both HLA-A*0201 binding and CTL recognition. Anchor replacements towards the HLA-A*0201 peptide-binding motif gave rise to peptides with higher HLA-A*0201 binding capacity compared to the wild-type epitope. In addition, several of the gp100 154-162 epitope-analogues were more efficient at target-cell sensitization for lysis by anti-gp100 154-162 CTL compared to the wild-type epitope. These altered gp100 154-162 epitopes were subsequently tested for their capacity to induce CTL responses in vivo using HLA-A*0201/Kb transgenic mice, and in vitro using HLA-A*0201 + donor-derived lymphocytes. Interestingly, the peptide-specific CTL obtained, which were raised against the different gp100 154-162 epitope-analogues, displayed cross-reactivity with target cells endogenously processing and presenting the native epitope. These data demonstrate that altered epitopes can be exploited to elicit native epitope-reactive CTL. The use of epitope-analogues with improved immunogenicity may contribute to the development of CTL-epitope based vaccines in viral disease and cancer.

Animals↗
PubMed1996

Priming of measles virus-specific CTL responses after immunization with a CTL epitope linked to a fusogenic peptide.

In this study, the potential of the amino-terminal sequence from the F1 polypeptide responsible for the fusion of measles virus (MV) with cell membranes as a carrier system for a CTL epitope from the MV nucleoprotein was examined. The addition of the fusion sequence (FP) at either the amino or the carboxyl terminus of the CTL epitope peptide rendered it immunogenic after intraperitoneal immunization in mice. The CTLs induced were able to lyse target cells pulsed with the peptide or persistently infected with MV. After intranasal administration of a FP-CTL chimera with or without cholera toxin B subunit (CTB) as an adjuvant, CTL responses to the peptide pulsed and to MV-infected target cells were detected. Responses in groups of mice where CTB was used as an adjuvant were stronger. However, intranasal administration of the CTL epitope did not induce a protective response against intracranial challenge with a neuroadapted strain of MV. These findings highlight the potential of fusion sequences as a carrier system for CTL epitopes and the potential of the intranasal route for administration of synthetic peptides representing MV sequences.

Amino Acid Sequence↗
PubMed1987

Class II antigen-specific murine cytolytic T lymphocytes (CTL). I. Analysis of bulk populations and establishment of Lyt-2+L3T4- and Lyt-2-L3T4+ bulk CTL lines.

Murine allogeneic cytolytic T lymphocytes (CTLs), including long-term bulk CTL lines, were induced in I-region-incompatible combinations of strains in vitro in order to study the phenotypes of class II major histocompatibility complex (MHC) antigen-specific CTLs, as well as the possible functional involvement of accessory cell interaction molecules such as Lyt-2 and L3T4. This report shows that class II-specific allogeneic CTL populations consist of two types of T cells. Lyt-2+L3T4- (2+4-) and Lyt-2-L3T4+ (2-4+), in variable proportions depending on the strain combination, that in vitro bulk CTL lines with each of these phenotypes can be established, that the killing function of 2-4+ CTL is sensitive to the blocking effect of anti-L3T4 antibodies, suggesting functional involvement of this molecule in the CTL-target interaction, that anti-Lyt-2 antibodies fail to block killing by 2+4- cells, suggesting that such CTLs do not utilize this molecule in their killing function, and that while I-A-specific CTLs of both phenotypes are detectable, 2-4+ cells could not be detected among I-E-specific CTL populations.

Animals↗
PubMed1994

An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein-Barr virus CTL epitope: implications for graft-versus-host disease.

The phenomenon of T cell allorecognition is difficult to accommodate within the framework of a T cell repertoire positively selected in the thymus, unless allorecognition results from the cross-reactions of self-major histocompatibility complex restricted T cells. Herein, we demonstrate the dual specificity of cytotoxic T lymphocyte (CTL) clones for the immunodominant Epstein-Barr virus (EBV) epitope FLRGRAYGL, presented on HLA-B8, and the alloantigen HLA-B*4402. CTL which recognized peptide FLRGRAYGL in association with HLA-B8 could be reactivated in vitro from healthy individuals who had been exposed previously to EBV, using stimulator cells expressing the cross-reacting alloantigen HLA-B*4402. Limiting dilution analysis of the alloresponse to HLA-B*4402 in eight healthy individuals revealed that HLA-B8+, EBV-sero+ donors had higher CTL precursor frequencies for alloantigen HLA-B*4402 than EBV-sero- control donors. It is surprising that the majority (65-100%) of anti-HLA-B*4402 CTL, generated in limiting dilution mixed lymphocyte reactions between responder cells from HLA-B8+, EBV-sero+ individuals and HLA-B*4402+ stimulators, also recognized the EBV CTL epitope FLRGRAYGL/HLA-B8. In contrast to previous studies showing extensive diversity in the T cell repertoire against individual alloantigens, these data demonstrate that the response to an alloantigen can be dominated by CTL cross-reactive with a single viral epitope, thus illustrating a possible mechanism for the frequent clinical association between herpesvirus exposure and graft-versus-host disease after bone marrow transplants.

Amino Acid Sequence↗
PubMed1997

Targeting of HIV-1 antigens for rapid intracellular degradation enhances cytotoxic T lymphocyte (CTL) recognition and the induction of de novo CTL responses in vivo after immunization.

CD8+ cytotoxic T lymphocytes (CTLs) have the ability to recognize and eliminate virally infected cells before new virions are produced within that cell. Therefore, a rapid and vigorous CD8+ CTL response, induced by vaccination, can, in principle, prevent disseminated infection in vaccinated individuals who are exposed to the relevant virus. There has thus been interest in novel vaccine strategies that will enhance the induction of CD8+ CTLs. In this study, we have tested the hypothesis that targeting an antigen to undergo more efficient processing by the class I processing pathway will elicit a more vigorous CD8+ CTL response against that antigen. Targeting a type I transmembrane protein, the HIV-1 envelope (env) protein, for expression in the cytoplasm, rather than allowing its normal co-translational translocation into the endoplasmic reticulum, sensitized target cells expressing this mutant more rapidly for lysis by an env-specific CTL clone. Additionally, a greatly enhanced de novo env-specific CTL response was induced in vivo after immunization of mice with recombinant vaccinia vectors expressing the cytoplasmic env mutant. Similarly, targeting a cytoplasmic protein, HIV-1 nef, to undergo rapid cytoplasmic degradation induced a greatly enhanced de novo nef-specific CD8+ CTL response in vivo after immunization of mice with either recombinant vaccinia vectors or DNA expression plasmids expressing the degradation targeted nef mutant. The targeting of viral antigens for rapid cytoplasmic degradation represents a novel and highly effective vaccine strategy for the induction of enhanced de novo CTL responses in vivo.

AIDS Vaccines↗
PubMed1996

Use of intrinsic and extrinsic helper epitopes for in vivo induction of anti-hepatitis C virus cytotoxic T lymphocytes (CTL) with CTL epitope peptide vaccines.

The induction of virus-specific cytotoxic T lymphocytes (CTL) is an important part of vaccine strategy. CTL induction in vivo by two hepatitis C virus (HCV) peptides containing CTL epitopes, one from the NS5 region (P17) and one from the core (C7), was compared. P17 required covalent attachment of a helper peptide (PCLUS3 containing a cluster of epitopes from the human immunodeficiency virus envelope protein), whereas C7 did not. However, the minimal decapeptide of C7, C7A10, alone did not induce CTL. The helper cells induced by PCLUS3-17 or by C7 were shown to be CD4+ and to produce interleukin-2 (IL-2). Thus, help can be supplied by a natural helper epitope intrinsic to the CTL peptide, as in C7, or by attaching a helper epitope from another protein, as in the case of P17. The cluster peptides may be useful promiscuous helper peptides for a variety of CTL epitopes from diverse pathogens.

Amino Acid Sequence↗
PubMed1998

CD40 ligand-mediated interactions are involved in the generation of memory CD8(+) cytotoxic T lymphocytes (CTL) but are not required for the maintenance of CTL memory following virus infection.

CD8(+) cytotoxic T lymphocytes (CTL) play a key role in the control of many virus infections, and the need for vaccines to elicit strong CD8(+) T-cell responses in order to provide optimal protection in such infections is increasingly apparent. However, the mechanisms involved in the induction and maintenance of CD8(+) CTL memory are currently poorly understood. In this study, we investigated the involvement of CD40 ligand (CD40L)-mediated interactions in these processes by analyzing the memory CTL response of CD40L-deficient mice following infection with lymphocytic choriomeningitis virus (LCMV). The maintenance of memory CD8(+) CTL precursors (CTLp) at stable frequencies over time was not impaired in CD40L-deficient mice. By contrast, the initial generation of memory CTLp was affected. CD40L-deficient mice produced lower levels of CD8(+) CTLp during the primary immune response to LCMV than did wild-type controls, despite the fact that the LCMV-specific effector CTL response of CD40L-deficient mice was indistinguishable from that of control animals. The differentiation of naïve CD8(+) T cells into effector and memory CTL thus involves pathways that can be discriminated from each other by their requirement for CD40L-mediated interactions. Expression of CD40L by CTLp themselves was not an essential step during their expansion and differentiation from naïve CD8(+) cells into memory CTLp; instead, the reduction in memory CTLp generation in CD40L-deficient mice was likely a consequence of defects in the CD4(+) T-cell response mounted by these animals. These results thus suggest a previously unappreciated role for CD40L in the generation of CD8(+) memory CTLp, the probable nature of which is discussed.

Animals↗
PubMed2004

Impaired processing and presentation of cytotoxic-T-lymphocyte (CTL) epitopes are major escape mechanisms from CTL immune pressure in human immunodeficiency virus type 1 infection.

Investigating escape mechanisms of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTLs) is essential for understanding the pathogenesis of HIV-1 infection and developing effective vaccines. To study the processing and presentation of known CTL epitopes, we prepared Epstein-Barr virus-transformed B cells that endogenously express the gag gene of six field isolates by adopting an env/nef-deletion HIV-1 vector pseudotyped with vesicular stomatitis virus G protein and then tested them for the recognition by Gag epitope-specific CTL lines or clones. We observed that two field variants, SLFNTVAVL and SVYNTVATL, of an A*0201-restricted Gag CTL epitope SLYNTVATL, and three field variants, KYRLKHLVW, QYRLKHIVW, and RYRLKHLVW, of an A24-restricted Gag CTL epitope KYKLKHIVW escaped from being killed by the CTL lines, despite the fact that they were recognized when the synthetic peptides corresponding to these variant sequences were exogenously loaded onto the target cells. Thus, their escape is likely due to the changes that occur during the processing and presentation of epitopes in the infected cells. Mutations responsible for this mode of escape were located within the epitope regions rather than the flanking regions, and such mutations did not influence the virus replication. The results suggest that the impaired antigen processing and presentation often occur in HIV-1 field isolates and thus are one of the major mechanisms that enable HIV-1 to escape from CTL recognition. We emphasize the importance of testing HIV-1 variants in an endogenous expression system.

Amino Acid Sequence↗
PubMed2004

Therapeutic polypeptides based on HBcAg(18-27) CTL epitope can induce antigen-specific CD(8)(+) CTL-mediated cytotoxicity in HLA-A2 transgenic mice.

AIM: To explore how to trigger an HLAI-restricted CD8(+) T cell response to exogenously synthesized polypeptides in vivo. METHODS: Three mimetic therapeutic polypeptides based on the immunodominant CTL epitope of HBcAg, the B- epitope of HBV PreS(2) region and a common T helper sequence of tetanus toxoid were designed and synthesized with Merrifield's solid-phase peptide synthesis method. Their immunological properties of inducing T( H1) polarization, CD8(+) HBV-specific CTL expansion and CD8(+) T cell mediated cytotoxicity were investigated in HLA-A2 transgenic mice. RESULTS: Results demonstrated that the mimetic polypeptides comprised of the immunodominant CTL, B-, and T helper epitopes could trigger specifically and effectively vigorous CD8(+) HBV-specific CTL-mediated cytotoxicity and T(H1) polarization of T cells in HLA-A2 transgenic mice. CONCLUSION: A designed universal T helper plus B-epitopes with short and flexible linkers could dramatically improve the immunogenicity of CTL epitopes in vivo. And that the mimetic therapeutic peptides based on the reasonable match of the above CTL, B- and T helper epitopes could be a promising therapeutic peptide vaccine candidate against HBV infection.

Animals↗
PubMed2000

CTL control of EBV in nasopharyngeal carcinoma (NPC): EBV-specific CTL responses in the blood and tumors of NPC patients and the antigen-processing function of the tumor cells.

Undifferentiated nasopharyngeal carcinoma (NPC) is latently infected with EBV and expresses a restricted number of viral proteins. Studies in healthy virus carriers have demonstrated that at least some of these proteins can act as targets for HLA class I-restricted CTLs. Therefore we have explored the possibility of a CTL-based therapy for NPC by characterizing EBV-specific CTL responses in 10 newly diagnosed NPC cases and 21 healthy virus carriers from Southeast Asia. Using the autologous EBV-transformed lymphoblastoid cell line, virus-specific CTL were reactivated in vitro from PBMC, cloned, and screened for cytotoxicity against target cells expressing individual EBV proteins from recombinant vaccinia vectors. EBV-specific CTLs were identified in 6 of 10 patients and 14 of 21 controls and mainly targeted the EBV nuclear Ag 3 (EBNA3) family of viral latent proteins. However, in 3 of 10 patients and 11 of 21 controls, CTLs specific for the NPC-associated protein LMP2 were also detected, albeit at low frequency. EBV-specific CTLs were detected in tumor biopsy material obtained from 3 of 6 of the patients, indicating that functional CTL are present at the tumor site, but none was specific for tumor-associated viral proteins. To assess the Ag-presenting function in NPC we studied two NPC-derived cell lines (C15 and c666.1) and demonstrated that both were capable of processing and presenting endogenously synthesized protein to HLA class I-restricted CTL clones. Overall, our data provide a sound theoretical basis for therapeutic strategies that aim to boost or elicit LMP2-specific CTL responses in NPC patients.

Adult↗
PubMed1999

EBV structural antigens, gp350 and gp85, as targets for ex vivo virus-specific CTL during acute infectious mononucleosis: potential use of gp350/gp85 CTL epitopes for vaccine design.

For many years, EBV vaccine development efforts have concentrated on the use of structural Ag, gp350, and have been directed toward Ab-mediated blocking virus attachment to the target cell. There is increasing evidence to suggest that the development of neutralizing Abs in vaccinated animals does not always correlate with protection; nevertheless, it has been postulated that gp350-specific T cell-mediated immune responses may have an effector role in protection. This hypothesis has largely remained untested. In the present study, we demonstrate that CTL from acute infectious mononucleosis patients display strong ex vivo reactivity against the EBV structural Ags, gp85 and gp350. Moreover, long-term follow up studies on infectious mononucleosis-recovered individuals showed that these individuals maintain gp350- and gp85-specific memory CTL, albeit at low levels, in the peripheral blood. These results strongly suggest that CTL specific for EBV structural proteins may play an important role in the control of EBV infection during acute infection. More importantly, we also show that prior immunization of HLA A2/Kb transgenic mice with gp350 and gp85 CTL epitopes induced a strong epitope-specific CTL response and afforded protection against gp85- or gp350-expressing vaccinia virus challenge. These results have important implications for future EBV vaccine design and provides evidence, for the first time, that CTL epitopes from EBV structural proteins may be used for establishing strong antiviral immunity against EBV infection.

Acute Disease↗
PubMed1983

Development and function of cytotoxic T lymphocytes (CTL). I. In vivo maturation of CTL precursors in the absence of detectable proliferation results as a normal consequence of alloimmunization.

In the experiments reported here, we examine the need for cell division as a critical component in the clonal expansion of alloreactive CTL precursors. Unlike previous attempts to inhibit DNA synthesis and cell division non-specifically, we have chosen to follow the normal unimpeded development of CTL in two of the most commonly used in vivo and in vitro allograft systems. The development and relative contribution of CTL lymphoblast-associated cytotoxicity has been followed by density gradient separation and functional analysis of the various fractions of lymphocytes obtained throughout the entire course of sensitization. In addition to the physical parameters (size and density), even more convincing data have been obtained from in vivo administration of 3H-TdR during the entire allograft reaction. The results presented here clearly confirm CTL precursor proliferation in vitro but provide strong evidence that in vivo CTL normally arise via a mechanism independent of blast formation and cellular proliferation. Interpretations of these findings in relationship to the concept of "clonal expansion" for the generation of mature CTL are discussed.

Animals↗
PubMed1995

In vivo state of antiviral CTL precursors. Characterization of a cycling cell population containing CTL precursors in immune mice.

The in vivo state of CD8+ mouse memory CTL specific to lymphocytic choriomeningitis virus (LCMV) was characterized. During acute LCMV infection, the majority of the LCMV-specific CTL activity tested immediately ex vivo was mediated by CD8+ L-selectin- Mac-1+ CTL. The L-selectin- population of CD8+ cells elicited during acute infection also carried > 99% of the restimulatable CD8+ CTL precursors (CTLp) to LCMV, and these required added IL-2 for development into effectors in vitro. In contrast with the acute infection, most of the virus-specific CTLp in immune mice were L-selectin+. Examination of CD8+ T cells in LCMV-immune mice revealed that a L-selectin+ blast-size population of cycling CD8+ cells contained CTLp, which developed into effector CTL in the absence of added IL-2. These cells also expressed Mac-1 and IL-2R. Flow cytometric sorting for IL-2R+ and IL-2R- CD8+ cells in the immune animal revealed, by limiting dilution analysis, similar frequencies of CTLp in both populations. In bulk restimulation assays, the CD25+ CTLp did not require added IL-2 for their in vitro development into effectors, whereas the CD25- CTLp did. Hence, the different requirements for CTLp to effector development in vitro reflect qualitative differences in the in vivo state of the CTLp in the various subpopulations. LCMV-specific memory CTLp that did not require added IL-2 for differentiation were also found in the small-size, noncycling, CD8+L-selectin- cells. In contrast, the small-size, noncycling, CD8+L-selectin+, and CD8+IL-2R- populations also carried CTLp, but these required added IL-2 for development into effector CTL. Hence, T cell memory to LCMV is distributed among various lymphocyte subpopulations in immune animals, and the presence of an activated cycling cell component may account for the long-term perpetuation of antiviral immunologic memory.

Animals↗
PubMed1985

Signal requirements for the in vitro differentiation of cytotoxic T lymphocytes (CTL): distinct soluble mediators promote preactivation of CTL-precursors, clonal growth and differentiation into cytotoxic effector cells.

We describe here that the requirement of accessory cells for the polyclonal activation of high-density (resting) murine T lymphocytes can be bypassed by soluble mediators present in culture supernatants of concanavalin A (Con A)-activated murine spleen cells. Induction of responsiveness is confined to Lyt-2+ T cells; GK 1.5+ T helper cells require signals provided by accessory cells. Using this system the lymphokine signal requirements for the polyclonal activation of Lyt-2+ cytotoxic T lymphocyte (CTL) precursors could be defined. We show that Con A fails to trigger in Lyt-2+ responder T cells the expression of interleukin 2 (IL 2) receptors and assume that this explains why recombinant (rec) DNA-derived IL 2 fails to induce proliferative responses. Complementation of rec IL 2 with an IL 2 receptor-inducing factor (RIF) induces proliferative responses. RIF alone triggers IL 2 receptor expression in 10-12% of Lyt-2+ T cells exposed to Con A. This lymphokine appears to be distinct from colony-stimulating factor 1, IFN-gamma and IL 1. Resting Lyt-2+ T cells cultured in limiting numbers in the presence of Con A, RIF plus rec IL 2 do proliferate, yet exhibit no cytolytic activity. Differentiation into CTL can be brought about by addition of cytotoxic T cell differentiation factor (CTDF). We conclude that the polyclonal activation pathway of CTL from resting CTL precursors can be subdivided into three stages: preactivation, clonal growth and CTL differentiation. Each of these stages appears to be controlled by a distinct lymphokine, RIF, IL 2 and CTDF, respectively.

Animals↗