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CD8+ T Cell Responses (cd8+ t + cell_response)
Selected AbstractsGenerating functional CD8+ T cell memory response under transient CD4+ T cell deficiency: Implications for vaccination of immunocompromised individualsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Corey Smith Abstract Studies based on either MHC class II-knockout or CD4+ T cell-depleted murine models have demonstrated a critical role for CD4+ T cells in the generation of CD8+ T cell memory. However, it is difficult to extend these findings to immunocompromised humans where a complete loss of CD4+ T cells is rarely observed. Here, we have developed a model setting, which allows studies on the generation of CD8+ T cell memory responses in a transient CD4+ T cell-deficient setting similar to that seen in immunocompromised patients. Immunisation with an adenoviral vaccine under transient helpless or help-deficient conditions showed varying degrees of impact on the priming of CD8+ T cell responses. Antigen-specific T cells generated under normal CD4+ T cell help and transient help-deficient conditions showed similar effector phenotype and were capable of proliferation upon secondary antigen encounter. Most importantly, in spite of CD4+ T cell deficiency, the long-term CD8+ T cell memory response remained functionally stable and showed comparable cytotoxic effector function as seen in CD8+ T cells generated with normal CD4+ T cell numbers. These findings provide evidence that in spite of partially impaired activation of a primary CD8+ T cell response, a fully functional and stable memory CTL response can be induced under conditions of severe transient CD4+ T cell deficiency. [source] Identification of a dengue virus-specific HLA-A*0201-restricted CD8+ T cell epitopeJOURNAL OF MEDICAL VIROLOGY, Issue 4 2010Jinsheng Wen Abstract In this study, a combination of epitope-prediction programs and in vitro assays was used to identify dengue virus (DENV)-specific CD8+ T cell epitopes. Peripheral blood mononuclear cells (PBMCs) isolated from patients who recovered from dengue fever were stimulated with candidate epitope peptides derived from DENV, which were predicted by using SYFPEITHI and RANKpep epitope-prediction programs. The IFN-, ELISpot results and the results of intracellular staining of IFN-, showed that peptides NS4b_40 (TLYAVATTI), E_256 (QEGAMHTAL), NS3_205 (LPAIVREAI), NS5_210 (SRNSTHEMY), and NS3_207 (AIVREAIKR) could induce the recall response of CD8+ T cells. Furthermore, the results of the MHC,peptide complex stabilization assay revealed that peptide NS4b_40 (TLYAVATTI) has a high affinity for HLA-A*0201 molecules. The IFN-, ELISpot results and staining of intracellular IFN-, confirmed that this peptide could induce high-level CD8+ T cell response in HLA-A*0201 positive PBMCs. Peptide NS4b_40 (TLYAVATTI) was identified as a novel DENV-specific HLA-A*0201-restricted CD8+ T cell epitope. J. Med. Virol. 82:642,648, 2010. © 2010 Wiley-Liss, Inc. [source] Analysis of a successful HCV-specific CD8+ T cell response in patients with recurrent HCV-infection after orthotopic liver transplantation,,LIVER TRANSPLANTATION, Issue 12 2004Norbert Hubert Gruener Virus-specific CD8+ T cells play a major role in antiviral immune defenses; their significance in the transplant setting, however, is unclear. In the present study, we asked whether hepatitis C virus (HCV)-specific CD8+ T cells were detectable in the presence of an immunosuppressive treatment and whether the HCV-specific CD8+ T cell response correlates with treatment outcome in patients who receive interferon (IFN)-, / ribavirin therapy after orthotopic liver transplantation (OLTx). Liver- and blood-derived T cell lines of 21 patients after OLTx were studied before, at the end of, and after antiviral treatment. Virus-specific IFN-, production in response to a panel of previously identified HCV-specific epitopes restricted by the human leukocyte antigen (HLA) class I molecules A2, A3, B7, B35, and B44 of structural and nonstructural HCV protein was determined by enzyme-linked immunospot (ELISPOT) assay. Before treatment, only low numbers of HCV-specific CD8+ T cells were detectable. In 6 patients with a sustained virological response, a significant, multispecific, and sustained CD8+ T cell response was detectable, which was mainly found in the peripheral blood. Nonresponders and transient responders showed undetectable, weak, or transient HCV-specific CD8+ T cell responses. (Sustained responders vs. transient and nonresponders: Wilcoxon rank-signed test; P < .01). In conclusion, our data indicate that despite immunosuppression, HCV-specific CD8+ T cells are detectable in patients with recurrent HCV infection after OLTx and that a significant, multispecific, and long-lasting HCV-specific CD8+ T cell response contributes to viral elimination. (Liver Transpl 2004;10:1487,1496.) [source] Studies of cell-mediated immune responses to influenza vaccination in systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 8 2009Albert Holvast Objective Both antibody and cell-mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell-mediated responses have not yet been assessed. This study was therefore undertaken to assess cell-mediated responses to influenza vaccination in patients with SLE. Methods Fifty-four patients with SLE and 54 healthy control subjects received subunit influenza vaccine. Peripheral blood mononuclear cells and sera were obtained before and 1 month after vaccination. Cell-mediated responses to A/H1N1 and A/H3N2 vaccines were evaluated using an interferon-, (IFN,) enzyme-linked immunospot assay and flow cytometry. Antibody responses were measured using a hemagglutination inhibition test. Results Prior to vaccination, patients with SLE had fewer IFN, spot-forming cells against A/H1N1 compared with control subjects and a lower frequency of IFN,-positive CD8+ T cells. After vaccination, the number of IFN, spot-forming cells increased in both patients and control subjects, although the number remained lower in patients. In addition, the frequencies of CD4+ T cells producing tumor necrosis factor and interleukin-2 were lower in patients after vaccination compared with healthy control subjects. As expected for a subunit vaccine, vaccination did not induce a CD8+ T cell response. For A/H3N2-specific responses, results were comparable. Diminished cell-mediated responses to influenza vaccination were associated with the use of prednisone and/or azathioprine. The increase in A/H1N1-specific and A/H3N2-specific antibody titers after vaccination was lower in patients compared with control subjects. Conclusion In addition to a decreased antibody response, cell-mediated responses to influenza vaccination are diminished in patients with SLE, which may reflect the effects of the concomitant use of immunosuppressive drugs. This may render these patients more susceptible to (complicated) influenza infections. [source] Generating functional CD8+ T cell memory response under transient CD4+ T cell deficiency: Implications for vaccination of immunocompromised individualsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Corey Smith Abstract Studies based on either MHC class II-knockout or CD4+ T cell-depleted murine models have demonstrated a critical role for CD4+ T cells in the generation of CD8+ T cell memory. However, it is difficult to extend these findings to immunocompromised humans where a complete loss of CD4+ T cells is rarely observed. Here, we have developed a model setting, which allows studies on the generation of CD8+ T cell memory responses in a transient CD4+ T cell-deficient setting similar to that seen in immunocompromised patients. Immunisation with an adenoviral vaccine under transient helpless or help-deficient conditions showed varying degrees of impact on the priming of CD8+ T cell responses. Antigen-specific T cells generated under normal CD4+ T cell help and transient help-deficient conditions showed similar effector phenotype and were capable of proliferation upon secondary antigen encounter. Most importantly, in spite of CD4+ T cell deficiency, the long-term CD8+ T cell memory response remained functionally stable and showed comparable cytotoxic effector function as seen in CD8+ T cells generated with normal CD4+ T cell numbers. These findings provide evidence that in spite of partially impaired activation of a primary CD8+ T cell response, a fully functional and stable memory CTL response can be induced under conditions of severe transient CD4+ T cell deficiency. [source] Intra-tumoral Salmonella typhimurium induces a systemic anti-tumor immune response that is directed by low-dose radiation to treat distal diseaseEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Francesca Avogadri Abstract Salmonella typhimurium is a facultative anaerobic bacterium able to multiply preferentially in tumors and inhibit their growth. The mechanisms through which Salmonella exerts its anti-cancer properties are not fully understood. We recently showed that intra-tumoral Salmonella injection results not only in the regression of even bulky tumor masses, but also impacts on the growth of distant untreated lesions. Here we describe how Salmonella exerts its systemic anti-cancer effects and means to potentiate them. The outburst of an early inflammatory reaction in the treated tumor promotes the development of an immunostimulatory cytokine environment both locally and in the draining lymph node. Within the next 10,days, an efficient cross-presentation of endogenous tumor antigens by dendritic cells at the tumor-draining lymph node leads to the priming of effective anti-tumor CD8+ T cell responses. This potentially broadly reactive T cell repertoire can be directed to other pre-established melanomas by low-dose radiotherapy enhancing the Salmonella anti-cancer effect. We demonstrate that Salmonella -based therapy coupled to low-dose radiotherapy dampens tumor immune escape mechanisms at different levels and allows controlling systemic disease in a CD8+ T cell-dependent manner. [source] Suppression of viral replication with highly active antiretroviral therapy has no impact on the functional profile of HIV-specific CD8+ T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2008Mariola López Abstract A better control of viral replication in long-term non-progressors has been associated with polyfunctional CD8+ T cell responses. However, low levels of HIV replication could be the cause rather than the consequence of enhanced immune responses in long-term non-progressors. The functional profile and the expansion ability of HIV-Gag- and HIV-Nef-specific CD8 responses were analysed measuring the production of MIP-1,, IL-2, TNF-, and expression of CD107, using polychromatic flow cytometry, in 36,HIV-infected patients at baseline and after 12,months of highly active antiretroviral therapy (HAART) and complete viral suppression. Most patients presented detectable Gag and Nef responses both at baseline and after 1,year of HAART, with a significant decline after achieving viral suppression. At baseline, the majority of CD8+ response was due to cells producing only MIP-1, or simultaneously MIP-1, and CD107. The functional profile did not significantly change after achieving complete viral suppression with HAART. Therefore, control of HIV-1 replication after 1,year of HAART had no significant impact on the quality of HIV-1-specific CD8 response, but the effects of treatment in long-term, or of early HAART are not known. Thus, it is still uncertain whether multifunctional CD8 responses are the cause or consequence of low plasma viremia. [source] Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infectionsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2007Martin Abstract IL-2 is a cytokine with multiple and even divergent functions; it has been described as a key cytokine for in vitro T cell proliferation but is also essential for down-regulating T cell responses by inducing activation-induced cell death as well as regulatory T cells. The in vivo analysis of IL-2 function in regulating specific T cell responses has been hampered by the fact that mice deficient in IL-2 or its receptors develop lymphoproliferative diseases and/or autoimmunity. Here we generated chimeric mice harboring both IL-2R-competent and IL-2R-deficient T cells and assessed CD8+ T cell induction, function and maintenance after acute or persistent viral infections. Induction and maintenance of CD8+ T cells were relatively independent of IL-2R signaling during acute/resolved viral infection. In marked contrast, IL-2 was crucial for secondary expansion of memory CD8+ T cells and for the maintenance of virus-specific CD8+ T cells during persistent viral infections. Thus, depending on the chronicity of antigen exposure, IL-2R signaling is either essential or largely dispensable for induction and maintenance of virus-specific CD8+ T cell responses. [source] Priming of CD8+ T cell responses by pathogens typically depends on CD70-mediated interactions with dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2007Anita Schildknecht Abstract The CD27/CD70-interaction has been shown to provide a costimulatory and survival signal for T cells in vitro and in vivo. Recently, CD70 expression by DC was found to be important for the priming of CD8+ T cells. We show here that blocking CD70 interactions has a significant impact on priming of CD8+ T cell responses by vaccinia virus (VV), Listeria monocytogenes and vesicular stomatitis virus (VSV) in mice. However, the priming of specific CD8+ T cells upon infection with lymphocytic choriomeningitis virus (LCMV) was only marginally reduced by CD70-blockade. Blocking of CD70 prevented CD8+ T cell priming in DIETER mice, a model in which presentation of LCMV-derived epitopes can be induced selectively in dendritic cells (DC). In contrast, CD70-CD27 interactions were not important for the priming of VSV-specific CD4+ T cells or class switch of neutralizing antibodies. As we show that priming of CD8+ T cells by the pathogens used here is dependent on antigen presentation by DC and that infection results in up-regulation of CD70 on DC, we conclude that CD70 expression on DC plays an important role in the priming of CD8+ T cells by pathogens. Moreover, the lack of CD70 cannot be completely compensated for by other costimulatory molecules. [source] IL-18, but not IL-12, is required for optimal cytokine production by influenza virus-specific CD8+ T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2007Alice Abstract The potent innate cytokines IL-12 and IL-18 are considered to be important antigen-independent mediators of IFN-, production by NK cells and T,lymphocytes. The present analysis addresses the physiological role of IL-12 and IL-18 in the generation of virus-specific CD8+ T cells. Both wt C57BL/6J (B6) mice and mice with disrupted IL-12p40 (IL-12p40,/,) or IL-18 (IL-18,/,) genes were infected with an influenza,A virus and the characteristics of the resultant epitope-specific CD8+ T cell responses were compared. While IL-12 appeared to have no notable effect on either virus growth or on CD8+ T cell response profiles, the absence of IL-18 was associated with delayed virus clearance from the lung and, despite normal numbers, a significantly reduced production of IFN-,, TNF-,, and IL-2 by epitope-specific CD8+ T cells. While this cytokine phenotype was broadly maintained in IL-12p40/IL-18 double-knockout mice, no evidence was seen for any additive effect. Together, our results suggest that IL-18, but not IL-12, induces optimal, antigen-specific production of key cytokines by CD8+ T cells for the efficient clearance of influenza virus from the lungs of infected mice. [source] Activated NKT cells increase dendritic cell migration and enhance CD8+ T cell responses in the skinEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Anton Abstract Activated NKT cells produce cytokines such as IL-4 and IFN-, that function locally to influence the strength and functional development of antigen-specific T cells. Here we identify an alternative mechanism by which NKT cells influence the strength of T cell responses: through modulation of peripheral dendritic cell (DC) trafficking. NKT cell activation with ,-galactosylceramide induced high systemic levels of TNF-, that mediated increased DC migration from skin to draining lymph nodes. This increased DC trafficking led to a threefold increase in effector T cell priming and in the immune response elicited to antigen challenge when ,-galactosylceramide was given at the time of immunization of the skin. These studies provide important implications for the use of NKT cell activation strategies to manipulate T cell-mediated responses including responses to cutaneous tumors and graft vs. host disease. [source] Human leukocyte antigen,associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution,HEPATOLOGY, Issue 2 2007Joerg Timm CD8+ T cell responses play a key role in governing the outcome of hepatitis C virus (HCV) infection, and viral evolution enabling escape from these responses may contribute to the inability to resolve infection. To more comprehensively examine the extent of CD8 escape and adaptation of HCV to human leukocyte antigen (HLA) class I restricted immune pressures on a population level, we sequenced all non-structural proteins in a cohort of 70 chronic HCV genotype 1a-infected subjects (28 subjects with HCV monoinfection and 42 with HCV/human immunodeficiency virus [HIV] coinfection). Linking of sequence polymorphisms with HLA allele expression revealed numerous HLA-associated polymorphisms across the HCV proteome. Multiple associations resided within relatively conserved regions, highlighting attractive targets for vaccination. Additional mutations provided evidence of HLA-driven fixation of sequence polymorphisms, suggesting potential loss of some CD8 targets from the population. In a subgroup analysis of mono- and co-infected subjects some associations lost significance partly due to reduced power of the utilized statistics. A phylogenetic analysis of the data revealed the substantial influence of founder effects upon viral evolution and HLA associations, cautioning against simple statistical approaches to examine the influence of host genetics upon sequence evolution of highly variable pathogens. Conclusion: These data provide insight into the frequency and reproducibility of viral escape from CD8+ T cell responses in human HCV infection, and clarify the combined influence of multiple forces shaping the sequence diversity of HCV and other highly variable pathogens. (HEPATOLOGY 2007.) [source] RNA-containing adenovirus/polyethylenimine transfer complexes effectively transduce dendritic cells and induce antigen-specific T cell responsesTHE JOURNAL OF GENE MEDICINE, Issue 4 2004Tatjana C. Gust Abstract Background Dendritic cells (DCs) are the most potent antigen-presenting cells in initiating primary immune responses. Given the unique properties of DCs, gene-modified DCs represent a particularly attractive approach for immunotherapy of diseases such as cancer. Methods Gene-modified DCs were obtained by a receptor-mediated gene delivery system using adenovirus (Ad) particles as ligand and RNA or DNA condensed by polyethylenimine (PEI). In vitro transcribed polyadenylated or non-polyadenylated RNA was used. RNA-transduced DCs were generated expressing chicken ovalbumin (OVA) or chimeric constructs thereof, and compared with DNA-transduced DCs. Results Ad/PEI transfection complexes efficiently delivered RNA into DCs. Such RNA-transduced DCs induced OVA-specific T cell responses more effectively than DNA-transduced DCs. Furthermore, DCs transduced with polyadenylated RNA were more potent in stimulating CD4+ and CD8+ T cell responses than DCs transduced with non-polyadenylated RNA and this was particularly important for CD4+ T cell responses. Conclusions Ad/PEI/RNA transfection is an efficient means for generating RNA-transduced DCs and for stimulating antigen-specific T cell responses. Polyadenylation of RNA enhances CD8+ T cell responses and is essential for CD4+ T cell responses. Copyright © 2004 John Wiley & Sons, Ltd. [source] Different Mechanisms of Cardiac Allograft Rejection in Wildtype and CD28-deficient MiceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2001Gregory L. Szot Although CD28 blockade results in long-term cardiac allograft survival in wildtype mice, CD28-deficient mice effectively reject heart allografts. This study compared the mechanisms of allogeneic responses in wildtype and CD28-deficient mice. Adoptive transfer of purified CD28-deficient T cells into transplanted nude mice resulted in graft rejection. However, this model demonstrated that the allogeneic T cell function was severely impaired when compared with wildtype T cells, despite similar survival kinetics. Cardiac allograft rejection depended on both CD4+ and CD8+ T cell subsets in CD28-deficient mice, whereas only CD4+ T cells were necessary in wildtype recipients. These results suggested that CD8+ T cells were more important in CD28-deficient than wildtype mice. In addition to the CD8+ T cell requirement, allograft rejection in CD28-deficient mice was dependent on a sustained presence of CD4+ T cells, whereas it only required the initial presence of CD4+ T cells in wildtype mice. Taken together, these data suggest that CD4+ T cells from CD28-deficient mice have impaired responses to alloantigen in vivo, thus requiring long-lasting cooperation with CD8+ T cell responses to facilitate graft rejection. These results may help to explain the failure to promote graft tolerance in some preclinical and clinical settings. [source] Infants with late breast milk acquisition of HIV-1 generate interferon-gamma responses more rapidly than infants with early peripartum acquisitionCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009B. Lohman-Payne Summary Infants infected with HIV-1 after the first month of life have a lower viral set-point and slower disease progression than infants infected before 1 month. We investigated the kinetics of HIV-1-specific CD8+ T lymphocyte secretion of interferon (IFN)-, in infants infected before 1 month of life compared with those infected between months 1 and 12 (late infection). HIV-1 infection was assessed at birth and at months 1, 3, 6, 9 and 12 and timing of infection was determined by HIV-1 gag DNA from dried blood spots and verified by plasma HIV-1 RNA levels. HIV-1 peptide-specific IFN-, responses were measured by enzyme-linked immunospot at months 1, 3, 6, 9 and 12. Timing of development of IFN-, responses was compared using the log,rank test and Kaplan,Meier survival curves. Infants infected late developed HIV-1-specific CD8+ T cell responses 2·8 months sooner than infants infected peripartum: 2·3 versus 5·1 months after HIV-1 infection (n = 52, P = 0·04). Late-infected infants had more focused epitope recognition than early-infected infants (median 1 versus 2 peptides, P = 0·03); however, there were no differences in the strength of IFN-, responses. In infants infected with HIV-1 after the first month of life, emergence of HIV-1-specific CD8+ IFN-, responses is coincident with the decline in viral load, nearly identical to what is observed in adults and more rapid than in early-infected infants. [source] | |||||||||||||||||||||||||