共查询到20条相似文献,搜索用时 15 毫秒
1.
Tynan FE Reid HH Kjer-Nielsen L Miles JJ Wilce MC Kostenko L Borg NA Williamson NA Beddoe T Purcell AW Burrows SR McCluskey J Rossjohn J 《Nature immunology》2007,8(3):268-276
Plasticity of the T cell receptor (TCR) is a hallmark of major histocompatibility complex (MHC)-restricted T cell recognition. However, it is unclear whether interactions of TCR and peptide-MHC class I (pMHCI) always conform to this paradigm. Here we describe the structure of a TCR, ELS4, in its non-ligand-bound form and in complex with a prominent 'bulged' Epstein-Barr virus peptide bound to HLA-B(*)3501. This complex was atypical of previously characterized TCR-pMHCI interactions in that a rigid face of the TCR crumpled the bulged antigenic determinant. This peptide 'bulldozing' created a more featureless pMHCI determinant, allowing the TCR to maximize MHC class I contacts essential for MHC class I restriction of TCR recognition. Our findings represent a mechanism of antigen recognition whereby the plasticity of the T cell response is dictated mainly by adjustments in the MHC-bound peptide. 相似文献
2.
Bertrand Huard Philippe Prigent Franck Pags Denis Bruniquel Frdric Triebel 《European journal of immunology》1996,26(5):1180-1186
T cell response to its antigen requires recognition by the T cell receptor together with a co-receptor molecule, either CD4 or CD8. Additional molecules have been identified that are capable of delivering the co-stimulatory signals provided by APC. Following T cell priming, a number of T cell activation antigens are expressed that may play a role in the inactivation phase of the T cell response. The lymphocyte activation gene (LAG)-3 protein and its counter-receptors, the major histocompatibility complex (MHC) class II molecules, are such activation antigens whose interaction may result in the down-regulation of the ongoing immune response. To investigate the role of LAG-3/class II molecule interaction, we produced a soluble form of LAG-3 by fusing the extracellular Ig domains of this membrane protein to the constant region of human IgG1 (LAG-31g). Here, we show a direct and specific binding of LAG-3Ig to class II molecules on the cell surface. In addition, we show that LAG-3/class II molecule interaction leads to the down-regulation of CD4+ Ag-specific T cell clone proliferation and cytokine secretion. This inhibitory effect is observed at the level of the effector cells and not the APC and is also found with anti-CD3 mAb, PHA + PMA or low-dose IL-2 driven stimulation in the absence of APC. These functional studies indicate that T cell MHC class II molecules down-regulate T cell proliferation following LAG-3 binding and suggest a role for LAG-3 in the control of the CD4+ T cell response. 相似文献
3.
Tynan FE Burrows SR Buckle AM Clements CS Borg NA Miles JJ Beddoe T Whisstock JC Wilce MC Silins SL Burrows JM Kjer-Nielsen L Kostenko L Purcell AW McCluskey J Rossjohn J 《Nature immunology》2005,6(11):1114-1122
Unusually long major histocompatibility complex (MHC) class I-restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to alphabeta T cell receptor (TCR)-MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC restriction, we have determined here the structure of a TCR in complex with HLA-B(*)3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR-peptide-MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR-MHC class I contacts defined a minimal 'generic footprint' of MHC-restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC restriction. 相似文献
4.
S. J. Rupert Vessey Dan H. Barouch Stephen N. McAdam Lynda G. Tussey Miles A. Davenport Christopher A. O'Callaghan John I. Bell Andrew J. McMichael Bent K. Jakobsen 《European journal of immunology》1997,27(4):879-885
T cell receptors (TCR) identify target cells presenting a ligand consisting of a major histocompatibility complex molecule (MHC) and an antigenic peptide. A considerable amount of evidence indicates that the TCR contacts both the peptide and the MHC components of the ligand. In fully differentiated T cells the interaction between the peptide and the TCR makes the critical contribution to eliciting a cellular response. However, during the positive selection of thymocytes the contribution of peptide relative to MHC is less well established. Indeed it has been suggested that the critical interaction for positive selection is between the TCR and the MHC molecule and that peptides can be viewed as either allowing or obstructing this contact. This predicts that a given TCR is capable of engaging multiple MHC/peptide complexes. In this study a system is described which detects simply engagement of the TCR by MHC/peptide complexes rather than the functional outcome of such interactions. Using this approach the extent to which peptides can influence contacts between the TCR and the MHC molecule has been examined. The results show that the TCR does in fact engage a wide range of ligands in an MHC-restricted but largely peptide-independent manner, suggesting that only a few peptides are able to prevent the TCR from contacting the MHC molecule. 相似文献
5.
Yoseph Ghendler Rebecca E. Hussey Torsten Witte Emiko Mizoguchi Linda K. Clayton Atul K. Bhan Shigeo Koyasu Hsiu-Chiang Chang Ellis L. Reinherz 《European journal of immunology》1997,27(9):2279-2289
To investigate negative selection events during intrathymic ontogeny, we established T cell receptor (TCR)-transgenic mice [N15tg/RAG-2?/? (H-2b)] expressing a single TCR specific for vesicular stomatitis virus nuclear octapeptide N52–59 (VSV8) in the context of the major histocompatibility complex (MHC) class I molecule, Kb. Administration of VSV8 in vivo induced apoptosis in less than 4 h, deleting the majority of immature double-positive (DP) thymocytes by 24 h. In contrast, DP TCRhigh as well as single-positive (SP) thymocytes were refractory to this death process. Moreover, DP TCRhigh cells differentiated into SP thymocytes in vitro and in vivo, maturing into functional cytotoxic T lymphocytes upon intrathymic transfer to β RAG 2?/? recipients. Hence, negative selection processes involving MHC-bound peptide ligands are operative only prior to the late DP thymocyte stage in this MHC class I-restricted TCR transgene system. 相似文献
6.
Christian Ertel Neil S. Millar Peter T. Emmerson Volker Schirrmacher Paul Von Hoegen 《European journal of immunology》1993,23(10):2592-2596
In attempt to increase the induction of peptide-specific cytolytic T cells (CTL) we investigated the effect of the Newcastle disease virus (NDV) hemagglutinin-neuraminidase (HN) gene product on the activation of peptide-specific CTL. Spleen cells of CH3 mice immunized against the influenza nucleoprotein peptide 50–63 (NP 50–63) were restimulated in vitro (i) with peptide-pulsed syngeneic fibroblast cells (Ltk?) as antigen-presenting cells, which were in addition (ii) infected with NDV or (iii) stably transfected with the HN cDN A of NDV. A greater than sixfold increase in peptide-specific CTL responses was observed in cultures restimulated with peptide-pulsed Ltk? cells which co-expressed viral hemagglutinin due to either infection or transfection. A similar augmentation was seen in CTL responses against other types of antigen (major histocompatibility complex alloantigens, minor histocompatibility antigens or tumor antigens) when suboptimal cultures were stimulated with the respective antigen-presenting cells modified by NDV infection. These findings suggest that NDV or viral HN expressed on antigen-presenting cells or tumor cells can exert a T cell co-stimulatory function. 相似文献
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8.
Sren Mouritsen Morten Meldal Ida Christiansen-Brams Henrik Elsner Ole Werdelin 《European journal of immunology》1994,24(5):1066-1072
To investigate the immunogenicity of glycopeptides, a peptide fragment from hen egg lysozyme, HEL(81–96)-Y (here named 1) which is immunogenic in H-2k mice and known to bind to the murine major histocompatibility complex (MHC) class II molecule Ek, was synthesized in five different glycosylated forms. The N-terminal serine of HEL(81–96)-Y was derivatized with D -glucose (2), maltotriose (3), and a branched D -glucose pentasaccharide (4). Furthermore, 1 was prepared with a central serine or asparagine derivatized with the branched D -glucose pentasaccharide (5) and GlcNAc (6), respectively. The ability of the five glycopeptides and the non-glycosylated peptide, labeled with 125I, to bind to the two MHC class II molecules, Ak and Ek, was studied using a gel filtration assay. None of them could bind to Ak. Neither 5 nor 6 were able to bind to Ek. Surprisingly 2, 3 and 4 bound better to Ek than did the non-glycosylated peptide 1. The increased binding varied depending on the type of oligosaccharide attached to the N terminus of the peptide. The better binding to Ek of glycopeptide 4 was found to be due to an increased association rate. The binding of 1 as well as 4 was optimal at pH 5.0. Functional studies showed that 4 was able to elicit a heteroclitic proliferative response from T cells of mice immunized with the native non-glycosylated peptide. Circular dichroism studies of 1 and 4 indicated a more unordered structure of 4 and a predominant α-helical conformation of 1, suggesting that the MHC class II molecule may bind to peptides which are in a non-α-helical conformation. These results demonstrate that glycosylation has considerable influence on peptide immunogenicity for T lymphocytes. 相似文献
9.
The ligands for alpha beta T cell receptors (alphabetaTCRs) are usually major histocompatibility complex (MHC) proteins bound to peptides. Although there is evidence that T cell receptor variable regions have been selected evolutionarily to bind MHC, the rules governing this interaction have not previously been apparent. However, recent solved structures of T cell receptors with related variable regions bound to MHC plus peptides suggest that some amino acids in variable region CDR1 and CDR2s almost always react in a consistent way with MHC. These amino acids may therefore have been selected evolutionarily to predispose T cell receptors toward recognition of MHC ligands. 相似文献
10.
11.
《Immunity》2022,55(6):982-997.e8
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12.
Class II major histocompatibility complex restriction of human T cell responses to short ragweed allergen, Amb a V 总被引:1,自引:0,他引:1
Although T cells are known to play a crucial role in the induction of IgE synthesis, the class II major histocompatibility complex (MHC) restriction of aeroallergen-induced T cell responses in humans is incompletely defined. We have previously shown that, in allergic Caucasoid individuals, HLA-DR2 and Dw2 (DR2.2) is strongly associated with specific IgE and IgG antibody responses to highly purified Ambrosia (ragweed) allergen, Amb a V, from the artemisiifolia (short) species. For example, 95% of IgE antibody responders to Amb a V were typed as DR2.2. In a novel study of the genetic control of T cell responses to the Amb a V allergen, we have investigated the MHC class II restriction specificity of three CD4, Amb a V-specific T cell clones derived from a DR2.2+ atopic patient, and a polyclonal Amb a V-reactive T cell line from another DR2.2+ patient. We observed proliferative responses of all three clones to Amb a V only when either HLA-DR2.2 or DR2, Dw12 (DR2.12; found on Mongoloid populations) was present on the antigen-presenting cells, regardless of the HLA-DQ phenotype of the cells. Moreover, the responses of T cell line and clones were abolished by anti-DR but not by anti-DQ nor by anti-DP monoclonal antibodies, and, significantly, anti-DR alpha/beta I2 (anti-DR alpha /beta Iw15/w16; anti-"DR2b") monoclonal antibody blocked, in a dose-dependent manner, the cloned T cell responses to Amb a V. These findings demonstrate that DR alpha/beta I2.2 (DR alpha/beta I1501) and DR alpha/beta I2.12 (DR alpha/beta I1502) are functional in the restriction of the T cell recognition of Amb a V. These findings also illustrate the power of the allergy model for definitive investigation of the molecular basis of the human immune response. 相似文献
13.
T cell receptors (TCRs) bind complexes of cognate major histocompatibility complex (MHC) and peptide at relatively low affinities (1-200 microM). Nevertheless, TCR-MHC-peptide interactions are usually specific for the peptide and the allele encoding the MHC. Here we show that to escape thymocyte negative selection, TCRs must interact with many of the side chains of MHC-peptide complexes as 'hot spots' for TCR binding. Moreover, even when the 'parental' side chain did not contribute binding affinity, some MHC-peptide residues contributed to TCR specificity, as amino acid substitutions substantially reduced binding affinity. The presence of such 'interface-disruptive' side chains helps to explain how TCRs generate specificity at low-affinity interfaces and why TCRs often 'accommodate' a subset of amino acids at a given MHC-peptide position. 相似文献
14.
Ftima da Conceio-Silva Blanca L. Perlaza Jacques A. Louis Pedro Romero 《European journal of immunology》1994,24(11):2813-2817
This report shows that lymphoid tissues of mice which have resolved a primary infection with Leishmania major contain parasite-specific major histocompatibility complex (MHC) class I-restricted cytolytic CD8+ T cell precusors that can be expanded after specific restimulation in vitro with syngeneic antigen-presenting cells pulsed with a cyanogen bromide digest of L. major. In H-2b mice, two distinct populations of CD8+ T cells were identified which both lysed target cells pulsed with L. major-derived peptides but were restricted by a different H-2b class I gene product. Interestingly, these two populations appear to recognize different parasite-derived peptides. It is noteworthy that one K°-restricted CD8+ T cell line was able to specifically lyse syngeneic macrophages infected with viable L. major, indicating that some L. major-derived peptides may reach the MHC class I pathway of presentation from the phagolysosomal compartment where the parasites are confined in infected macrophages. The importance of these parasite-specific MHC class I restricted cytolytic CD8+ T cells for the elimination of L. major by the infected host remains to be determined. 相似文献
15.
In an attempt to define the binding of staphylococcal enterotoxin D (SED) to the T cell receptor Vbeta (TCR Vbeta) and major histocompatibility complex (MHC) class II molecules, site-directed mutagenesis has been used to introduce alanine substitutions at Asn23, Phe45, Leu59, Asn61, Ile92 and Phe203 in SED. SED-N23A (SEA with Asn23 replaced with alanine) and SED-F45A mutants exhibit a significantly reduced ability to induce T cell proliferation. However, SED-L59A, SED-N61A, SED-I92A and SED-F203A mutants exhibit the normal mitogenic activity. The ability binding to MHC class II and the TCR Vbeta specificity of SED-N23A and SED-F45A were then detected. SED-N23A, but not SED-F45A, was able to compete effectively with FITC-conjugated SED for binding to Raji cells. This finding indicates that the mitogenic activity defection of SED-N23A is not due to poor binding to SED-MHC class II molecules. When stimulated with SED-N23A, T cells bearing TCR Vbeta5 were significantly reduced. When stimulated with SED-F45A, T cells bearing TCR Vbeta5, TCR Vbeta8 and TCR Vbeta12.1 were all significantly reduced. These results suggest Asn23 is an important residue involved SED interacting with TCR Vbeta; Phe45 is required for effective interaction with MHC class II molecules; and the ability of SED stimulating certain TCR Vbeta+ T cells is dependent on Phe45 binding to MHC class II molecules. 相似文献
16.
Lazoura E Lodding J Farrugia W Ramsland PA Stevens J Wilson IA Pietersz GA Apostolopoulos V 《Immunology》2006,119(3):306-316
Designing peptide-based vaccines for therapeutic applications in cancer immunotherapy requires detailed knowledge of the interactions between the antigenic peptide and major histocompatibility complex (MHC) in addition to that between the peptide-MHC complex and the T-cell receptor. Past efforts to immunize with high-affinity tumour-associated antigenic peptides have not been very immunogenic, which may be attributed to the lack of T cells to these peptides, having been deleted during thymic development. For this reason, low-to-medium affinity non-canonical peptides represent more suitable candidates. However, in addition to the difficulty in identifying such antigens, peptide binding to MHC, and hence its ability to induce a strong immune response, is limited. Therefore, to enhance binding to MHC and improve immune responses, anchor modifications of non-canonical tumour-associated peptides would be advantageous. In this study, the non-canonical tumour-associated peptide from MUC1, MUC1-8 (SAPDTRPA), was modified at the MHC anchor residues to SAPDFRPL (MUC1-8-5F8L) and showed enhanced binding to H-2Kb and improved immune responses. Furthermore, the crystal structure of MUC1-8-5F8L in complex with H-2Kb was determined and it revealed that binding of the peptide to MHC is similar to that of the canonical peptide OVA8 (SIINFEKL). 相似文献
17.
Anette Stryhn Lars stergaard Pedersen Vianney Ortiz-Navarrete Sren Buus 《European journal of immunology》1994,24(6):1404-1409
A panel of antigen-specific, major histocompatibility complex class I-restricted T cell hybridomas has been generated to examine the capacity of peptide/class I complexes to stimulate T cells at the molecular level. Peptide/class I complexes were generated in detergent solution, purified and quantitated. Latex particles were subsequently coated with known amounts of preformed complexes and used to stimulate the T cell hybridomas. Stimulation was specific, i.e. only the appropriate peptide/class I combination were stimulatory, and quite sensitive, i.e. as little as 300 complexes per bead could be detected by the T cells. Preformed complexes were about 500000 times more potent than free peptide in terms of T cell stimulation, demonstrating the physiological relevancy of the biochemically generated complexes. Surprinsingly, the majority (including the most sensitive of the hybridomas) had lost CD8 expression, suggesting that antigen-specific stimulation of class I-restricted T cell hybridomas, as assessed by IL-2 release, does not depend on CD8. 相似文献
18.
David M. Ojcius Franois Godeau Jean-Pierre Abastado Jean-Laurent Casanova Philippe Kourilsky 《European journal of immunology》1993,23(5):1118-1124
Cytotoxic T lymphocytes (CTL) recognize peptides in association with major histocompatibility complex (MHC) class I proteins, but how peptides bind to class I is not well understood. We used a fluorescence technique to measure antigenic peptide binding to a soluble, single-chain Kd (SC-Kd) molecule in which the Kd heavy chain was connected by a 15-residue link to β2-microglobulin. Peptides were covalently labeled at their N terminus with dansyl, and binding of dansylated Kd-restricted peptides to SC-Kd resulted in significant fluorescence enhancement, which could be inhibited by unmodified Kd-restricted peptides. Real-time binding of a dansylated peptide could be followed by monitoring the fluorescence at 530 nm. The dansylated Plasmodium berghei circumsporozoite (PbCS) 263–260 peptide bound to “empty” SC-Kd with an association rate constant of 1140 M?1s?1, and the subsequent spontaneous dissociation of the SC-Kd-peptide complex was slow. The dissociation increased dramatically after addition of excess unlabeled PbCS 253–260 peptide, but with a slower association constant for unlabeled peptide, 77 M?1s?1. Thus, the Kd-peptide complex on the surface of antigen-presenting cells should be stable, but high concentrations of peptides in the endoplasmic reticulum (ER) lumen would allow for peptide exchange on Kd before export to the surface. The apparent activation energy for PbCS 253–260 peptide binding to SC-Kd was 6.78 ± 0.64 kcal/mole, similar to values previously reported for antigen-antibody interactions. 相似文献
19.
A panel of independent BALB/c T cell clones responding to a peptide of the lambda 2(315) immunoglobulin light chain (residues 91-101), in the context of I-Ed, has previously been described. A monoclonal antibody (mAb; GB113) to the T cell receptor (TcR) of one of the clones, 4B2A1 (V alpha 1, J alpha 19; V beta 8.2, D beta 1.1, J beta 1.2) precipitates the alpha/beta heterodimer from 4B2A1. However, GB113 does not bind DO11-10.2 cells bearing a similar alpha/beta heterodimer (V alpha 1.1, J alpha TT11; V beta 8.2, D beta 1.1, J beta 1.1). GB113 does not cross-react with the TcR of the six other clones in the panel. Furthermore, the mAb does not bind polyclonal lambda 2(315)-specific T cell lines except 4.4% of cells of line 4 from which 4B2A1 was cloned. The mAb only binds a negligible number (0.5%) of BALB/c thymocytes and peripheral T cells. Therefore, the epitope detected by GB113 is very rarely expressed on 91-101. lambda 2(315)-specific TcR or on TcR of normal T cells. Soluble GB113 induces T cell activation [measured as proliferation and interleukin (IL) 2, IL3 and interferon-gamma production]. GB113-induced T cell activation is enhanced by soluble anti-CD4 and anti-Thy-1 mAb. 相似文献
20.
HLA-G: a tolerance molecule from the major histocompatibility complex 总被引:39,自引:0,他引:39