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CD8+ Cytotoxic T Lymphocytes (cd8+ + cytotoxic_t_lymphocyte)
Selected AbstractsRequirement for Q226, but not multiple charged residues, in the class I MHC CD loop/D strand for TCR-activated CD8 accessory functionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2003Micheal Durairaj Abstract Activation of CD8+ cytotoxic T lymphocytes typically begins with recognition of class I MHC-peptide complexes by the TCR and CD8 as a coreceptor. In its coreceptor role, CD8 binds thesame class I-peptide antigen complex as the TCR, enhancing the strength of TCR-class I interaction. Subsequent to initial TCR engagement, CD8 acts as an accessory molecule by binding any properly conformed class I molecules on the target cell surface, leading to CD8-mediated adhesion and cosignaling functions. We expressed and isolated a number of mutant class I molecules in which one or moreacidic or polar residues in the class I ,3 domain CD loop and D strand region, or ,2 domain were altered. Using solid phase CTL adhesion and degranulation assays with isolated class I molecules, we demonstrate that multiple acidic residues in the ,3 domain, although involved in CD8 coreceptor interaction, are not required for TCR-activated CD8 accessory interactions. Instead, we show that Q226, a polar group on the end of the CD loop, is required for TCR-activated CD8 accessory functions. These results indicate that CD8 coreceptor and accessory interactions differ substantially and suggest that TCR activation results in changes that alter the structural constraints for CD8 accessory interactions. [source] Pathogen evasion strategies for the major histocompatibility complex class I assembly pathwayIMMUNOLOGY, Issue 1 2008Antony N. Antoniou Summary Major histocompatibility complex (MHC) class I molecules bind and present short antigenic peptides from endogenously or exogenously derived sources to CD8+ cytotoxic T lymphocytes (CTL), with recognition of a foreign peptide normally targeting the cell for lysis. It is generally thought that the high level of MHC polymorphism, which is concentrated mostly within the peptide-binding groove, is driven by the ,evolutionary arms race' against pathogens. Many pathogens have developed novel and intriguing mechanisms for evading the continuous sampling of the intracellular and intercellular environments by MHC molecules, none more so than viruses. The characterization of immunoevasion mechanisms has improved our understanding of MHC biology. This review will highlight our current understanding of the MHC class I biosynthetic pathway and how it has been exploited by pathogens, especially viruses, to potentially evade CTL recognition. [source] Analysis of the mechanism for extracellular processing in the presentation of human immunodeficiency virus-1 envelope protein-derived peptide to epitope-specific cytotoxic T lymphocytesIMMUNOLOGY, Issue 1 2000Y. Nakagawa Summary An immunodominant epitope of human immunodeficiency virus-1 (HIV-1) gp160 recognized by Dd class I major histocompatibility complex (MHC) molecule-restricted, CD8+ cytotoxic T lymphocytes (CTL) was originally identified as a peptide composed of 15 amino acids (P18IIIB: RIQRGPGRAFVTIGK). However, further study has indicated that a 10-mer peptide, I-10 (RGPGRAFVTI), within P18IIIB is the minimal-sized epitope and the trimming step(s) of two carboxyl terminal amino acids (GK) is essential to produce I-10 from P18IIIB. In the processing, angiotensin-1-converting enzyme (ACE), found in sera, plays a central role in generating I-10. Target cells could be sensitized with I-10 under conditions where ACE activity in the sera was abrogated. In contrast, in the case of P18IIIB, requiring further processing to delete the C-terminus of two amino acids in order to act, sensitization of target cells was completely abrogated under the conditions. Pretreatment of target cells with brefeldin A (BFA), preventing the presentation of endogenous antigens from the class I MHC molecule pathway, did not inhibit the presentation of P18IIIB. Moreover, glutaraldehyde-fixed cells, which can not process native protein, though they could present the exogenously added peptides, were also sensitized by P18IIIB. These results clearly demonstrate that the fine processing to produce I-10 occurred in the extracellular milieu. Furthermore, our result suggests that the longer P18IIIB can bind to the class I molecules on the cell surface, and then be trimmed by ACE while it is bound. The mechanisms behind the extracellular processing outlined in this paper will offer important information for designing peptide-based vaccines to elicit MHC molecule-restricted effectors. [source] Paraflagellar rod protein-specific CD8+ cytotoxic T lymphocytes target Trypanosoma cruzi -infected host cellsPARASITE IMMUNOLOGY, Issue 8 2002Ruth A. Wrightsman Summary Our previous studies show that in mice immunized with the paraflagellar rod (PFR) proteins of Trypanosoma cruzi protective immunity against this protozoan parasite requires MHC class I-restricted T cell function. To determine whether PFR-specific CD8+ T cell subsets are generated during T. cruzi infection, potential CTL targets in the PFR proteins were identified by scanning the amino acid sequences of the four PFR proteins for regions of 8,10 amino acids that conform to predicted MHC class I H-2b binding motifs. A subset of the peptide sequences identified were synthesized and tested as target antigen in 51Cr-release assays with effector cells from chronically infected T. cruzi mice. Short-term cytotoxic T lymphocyte (CTL) lines specific for two of the peptides, PFR-1164,171 and PFR-3123,130, showed high levels of lytic activity against peptide-pulsed target cells, secreted interferon (IFN)-, in response to parasite-infected target cells, and were found to be CD8+, CD4,, CD3+, TCR,,+ cells of the Tc1 subset. Challenge of PFR immunized CD8,/, and perforin-deficient (PKO) mice confirmed that while CD8+ cells are required for survival of T. cruzi challenge infection, perforin activity is not required. Furthermore, while lytic activity of PFR-specific CD8+ T cell lines derived from PKO mice was severely impaired, the IFN-, levels secreted by CTLs from PKO mice were equivalent to that of normal mice, suggesting that the critical role played by CD8+ T cells in immunity to the parasite may be secretion of type 1 cytokines rather than lysis of parasite infected host cells. [source] Genetic approaches for the induction of a CD4+ T cell response in cancer immunotherapyTHE JOURNAL OF GENE MEDICINE, Issue 6 2005Aude Bonehill Abstract Recently, it has become more and more obvious that not only CD8+ cytotoxic T lymphocytes, but also CD4+ T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4+ T helper cells, and in particular IFN-,-secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development. Copyright © 2005 John Wiley & Sons, Ltd. [source] Natural Antigenic Peptides from Squamous Cell Carcinoma Recognized by Autologous HLA-DR8,restricted CD4+ T CellsCANCER SCIENCE, Issue 8 2002Hiroaki Kondo A large number of human tumor antigens recognized by CD8+ cytotoxic T lymphocytes (CTL) have been identified. Some of them have been employed in clinical trials and have achieved some objective responses. However, little is known about those that are recognized by CD4+ T cells, except for a very few that were identified from melanomas. Previously, we reported that an oral squamous cell carcinoma (SCC) cell line, OSC,20, was effectively lysed by HLA-DRB1·08032 (HLA-DRS)-restricted autologous CD4+ T cell line, TcOSC,20. In this study, we performed two steps of chromatographic purification of the tumor cell lysate in combination with mass spectrometry. We found one reverse-phase high-performance liquid chromatography (RP-HPLC) fraction that was effectively recognized by the T cells. We analyzed the fraction by nano-liquid chromatography/electrospray ionization ion trap mass spectrometry (LC/MS/MS) and found six representative ions. We could determine the primary amino acid sequence of each of the six ions. Three of them contained a potential HLA-DR8 binding motif, and TcOSC,20 showed a rather strong cytotoxic response to one of the synthetic pep tides, namely, amino acid residues 321,336 of human a-enolase. Thus, several gene products of squamous cancer cells are endogenously processed and may be presented on HLA class II molecules, so that they could constitute target molecules for autologous CD4+ T cells. [source] | ||||||||||