A Common TCR V-D-J Sequence in Vβ13.1 T Cells Recognizing an Immunodominant Peptide of Myelin Basic Protein in Multiple Sclerosis (original) (raw)
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Journal of immunology (Baltimore, Md. : 1950), 1999
T cell responses to the immunodominant peptide (residues 83-99) of myelin basic protein are potentially associated with multiple sclerosis (MS). This study was undertaken to examine whether a common sequence motif(s) exists within the TCR complementarity-determining region (CDR)-3 of T cells recognizing the MBP83-99 peptide. Twenty MBP83-99-reactive T cell clones derived from patients with MS were analyzed for CDR3 sequences, which revealed several shared motifs. Some V beta 13.1 T cell clones derived from different patients with MS were found to contain an identical CDR3 motif, V beta 13.1-LGRAGLTY. Oligonucleotides complementary to the shared CDR3 motifs were used as specific probes to detect identical target CDR3 sequences in a large panel of T cell lines reactive to MBP83-99 and unprimed PBMC. The results revealed that, in contrast to other CDR3 motifs examined, the LGRAGLTY motif was common to T cells recognizing the MBP83-99 peptide, as evident by its expression in the majorit...
International Immunology, 1998
T cell responses to myelin basic protein (MBP) are thought to play an important role in the pathogenesis of multiple sclerosis (MS). The response to the 83-99 region of MBP represents a dominant response to MBP in patients with MS and is associated with HLA-DR2 that is linked with susceptibility to MS. Although T cell clones reactive to various regions of MBP have been found to exhibit heterogeneous TCR V β gene usage in patients with MS, it is unclear whether T cell clones uniformly recognizing the 83-99 peptide of MBP in the context of the same DR molecule would have restricted TCR V gene rearrangements and recognition motifs. In this study, a panel of DR2or DR4-restricted T cell clones specific for the MBP83-99 peptide were derived from 11 patients with MS and examined for TCR V gene usage by PCR and the recognition motifs using analog peptides. Our study revealed that despite a few T cell clone pairs having similar recognition motifs and shared sequence homology in the CDR3, the overall recognition motifs of MBP83-99-specific T cells were considerably diverse. Interestingly, the DR2-restricted T cell clones displayed a biased V gene usage for V α 3 and V α 8, while V β gene rearrangements were highly heterogeneous. This study provided experimental evidence suggesting a limited heterogeneity in TCR V α gene rearrangements of MBP-reactive T cells in DR2 patients with MS.
Journal of Neuroimmunology, 1999
We selected two multiple sclerosis MS patients, compatible for HLA-DR2 subtype, and differing for HLA-DM haplotype as well as Ž . Ž . Ž for the myelin basic protein MBP epitope recognized by the vast majority of their T cell lines TCL residues 16-38 and 86-99, . respectively . TCL sharing the same restriction element were re-assayed in the presence of reciprocally mismatched antigen-presenting Ž . cells APC . The TCL recognized both the whole MBP and the relevant peptide also in the presence of non-autologous APC, Ž . compatibility for processing, despite a difference in the DM haplotype . The same protocol, performed in serum-free pulsing experiments or in the presence of 'fixed' APC, excluded extracellular processing or mutual T cell presentation, and confirmed the need for MBP Ž processing in our system. The finding, that only TCL recognizing MBP peptide 16-38 a region not previously related to the DR2 . haplotype used a novel Vb, supports the importance of the TCR repertoire over the processing-presentation machinery in the selection of MBP epitopes in MS. q
European Journal of Immunology, 1993
T lymphocytes from patients with multiple sclerosis (MS) recognize multiple myelin basic protein (MBP) epitopes. This situation complicates the design of specific immunotherapies. We investigated to which extent the T cell response to MBP is heterogeneous in single subjects in terms of preferentially recognized regions of the molecule, major histocompatibility complex (MHC) restriction, and stability over time. From each of nine patients with MS, a minimum of six MBP-specific T lymphocyte lines (TLL) were assayed for the proliferative response to a panel of overlapping peptides, encompassing the whole MBI? Predominant T cell recognitions of distinct MBP regions were present in three patients, all HLA-DR2+, independently of the clinical features of their disease. Tcell reactivity was preferentially directed to residues 16-38 in one patient. In this case the response was also stable over time, during different phases of the disease. Predominant reactivity to residues 86-99 was detected in the two other DR2+ patients. In each of the patients with other HLA-DR haplotypes (DR2-), as well as in three DR2+ non-MS donors, theTcell response to MBP appeared to be considerably more heterogeneous.The HLA restriction element varied among TLL recognizing the same MBP region, even when raised from the same individual. The genomic HLA typing, performed on the DRBl and DRBS genes in the DR2+ subjects, showed no obvious correspondence between preferential responses to regions of MBP and HLA-DR2 subtypes. In this context, a simple, new method for the genomic typing of the HLA-DRB1 gene in individuals with the HLA-DR2 serological specificity is also described. We conclude that predominant and stable T cell responses to a single MBP region can be detected in some patients with MS. In these individuals, the MHC restriction of theT cell recognition of predominant regions appears to be variable. Polymorphisms of the HLA-DR2 gene products alone do not account for the selection of the dominant MBP Tcell epitope.
Journal of Clinical Investigation, 1997
The structural requirements for autoantibody recognition were compared to those previously defined for MBP-specific T cell clones. MBP autoantibodies were affinity-purified from central nervous system lesions of 11/12 postmortem cases studied. The MBP(83-97) peptide was immunodominant in all 11 cases since it inhibited autoantibody binding to MBP Ͼ 95%. Residues contributing to autoantibody binding were located in a 10-amino acid segment (V86-T95) that also contained the MHC/T cell receptor contact residues of the T cell epitope. In the epitope center, the same residues were important for antibody binding and T cell recognition. Based on the antibody-binding motif, microbial peptides were identified that were bound by purified autoantibodies. Autoantibody binding of microbial peptides required sequence identity at four or five contiguous residues in the epitope center. Microbial peptides previously found to activate T cell clones did not have such obvious homology to MBP since sequence identity was not required at MHC contacts. The similar fine specificity of B cells and T cells may be useful for tolerance induction
Journal of Neuroimmunology, 1993
As has been indicated in experimental autoimmune encephalomyelitis (EAE), the application of synthetic peptides for the selection of T cell lines may provide new insights into the pathogenesis of multiple sclerosis (MS). We report here on T cell lines/clones generated from peripheral blood of MS patients against an immunodominant myelin basic protein (MBP) peptide 82-102. This study demonstrates that the selection of T cell lines against the MBP peptide is much more efficient than against whole MBP in generating a large panel of T cell lines/clones, and therefore provides a powerful strategy for studying autoimmune T cell repertoire in individual subjects. The peptide-selected lines and clones recognized MBP 82-102, shorter peptides MBP 89-101, 89-100 and guinea pig whole MBP mainly in the context of HLA-DR, but did not cross-recognize virus-derived peptides homologous to MBP 82-102. Seven out of ten clones were found to recognize MBP 82-102 in the absence of autologous antigen presenting cells (APC), and in three of the seven clones, specificity for MBP 82-102 could be demonstrated only in the absence of APC because of their strong reactivity against autologous APC. Two-color flow cytometry revealed that the clones were heterogeneous with regard to expression of CD4 and CD8 molecules. Overall, the clones selected by the peptide were rather heterogeneous in phenotype and function compared with those selected by whole MBP.
Journal of Experimental Medicine, 1991
We have examined previously the peptide specificity of the T cell response to myelin basic protein (MBP) in patients with multiple sclerosis (MS) and healthy controls, and demonstrated that an epitope spanning amino acids 87-106 was frequently recognized. Because this region is encephalitogenic in some experimental animals, it has been postulated that the response to the epitope may have relevance to MS. In this study, the fine specificity of this response is studied using four well-characterized, monospecific T cell lines from three MS patients and an identical twin of a patient. Each of the lines recognized a peptide with the same core sequence, amino acids 89-99, although the responses were affected to various degrees by truncations at the COOH- or NH2 terminal ends of the 87-106 epitope. Importantly, the epitope was recognized in conjunction with four different HLA-DR molecules. Also, the T cell receptor beta chain usage was heterogeneous, and each line expressed a different VDJ...
European Journal of Immunology, 2001
The common marmoset Callithrix jacchus (C. jacchus) is an outbred species characterized by a naturally occurring bone marrow chimerism and susceptibility to a form of experimental autoimmune encephalomyelitis (EAE) resembling multiple sclerosis (MS). T cell clones specific for the myelin antigen, myelin basic protein (MBP), can be derived from both naive and immunized marmosets and can adoptively transfer EAE to compatible chimeric siblings. Here, we demonstrate that severel different antigenic determinants of MBP are recognized by these encephalitogenic T cell clones. Furthermore, PCR-based analysis of TCR V g families does not show the preferential usage of any gene segment. Characterization of third complementarity determining regions (CDR3) fails to demonstrate a recurring motif characteristic of the T cell immune response to MBP in this species. Nevertheless, brief amino acid motifs are shared among marmoset clones and CDR3 sequences from MS samples. These data suggest that, due to its outbred condition, the C. jacchus marmoset mounts a diverse pathogenic response to MBP. However, the findings that certain CDR3 sequences are identically expressed in different animals, or by different T cell clones, suggest that MBP-specific T cell populations may be clonally expanded following chronic antigenic stimulation in vivo.
Clinical and Experimental Immunology, 2001
We studied the relationship between the HLA specificities associated with multiple sclerosis (MS) susceptibility in southern Italy and the reactivity of the human myelin basic protein (hMBP) immunogenic peptides 84±98 and 143±168, using short-term T-cell lines established from 9 MS patients and from 8 healthy individuals. In our population, DR15 was significantly associated with MS (34´9% in MS versus 13´7% in healthy controls, P , 0´05). This result is in agreement with the association found in northern Europe, but not with data obtained in a population from the island of Sardinia (Italy). In MS patients the frequency of reactive T-cell lines (TCL), tested for fine specificity against the immunodominant hMBP peptides 84±98 and 143±168, was increased for the hMBP 143±168 peptide (P , 0´05) but not for the 84±98 peptide. Although this reactivity was higher in DR15 1 MS patients than in DR 15 2 MS patients, it seemed not to be associated with DR15 specificity in the MS population. Furthermore, there were no significant differences in frequency of reactive TCL to hMBP peptide 84±98 in DR15-positive or DR15-negative MS patients. Consequently, it appears that peptide 84±98, considered as a relevant autoantigen, is not implicated in the pathogenesis of MS in our population from southern Italy.
Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis
The Journal of Immunology, 2004
Autoreactive T cells of CD4 and CD8 subsets recognizing myelin basic protein (MBP), a candidate myelin autoantigen, are thought to contribute to and play distinct roles in the pathogenesis of multiple sclerosis (MS). In this study we identified four MBP-derived peptides that had high binding affinity to HLA-A2 and HLA-A24 and characterized the CD8 ؉ T cell responses and their functional properties in patients with MS. There were significantly increased CD8 ؉ T cell responses to 9-mer MBP peptides, in particular MBP 111-119 and MBP 87-95 peptides that had high binding affinity to HLA-A2, in patients with MS compared with healthy individuals. The resulting CD8 ؉ T cell lines were of the Th1 phenotype, producing TNF-␣ and IFN-␥ and belonged to a CD45RA ؊ /CD45RO ؉ memory T cell subset. Further characterization indicated that the CD8 ؉ T cell lines obtained were stained with MHC class I tetramer (HLA-A2/MBP 111-119) and exhibited specific cytotoxicity toward autologous target cells pulsed with MBP-derived peptides in the context of MHC class I molecules. These cytotoxic CD8 ؉ T cell lines derived from MS patients recognized endogenously processed MBP and lysed COS cells transfected with genes encoding MBP and HLA-A2. These findings support the potential role of CD8 ؉ CTLs recognizing MBP in the injury of oligodendrocytes expressing both MHC class I molecules and MBP.