Immunodominance of a low-affinity major histocompatibility complex-binding myelin basic protein epitope (residues 111-129) in HLA-DR4 (B10401) subjects is associated with a restricted T cell receptor repertoire

• Published in: The Journal of clinical investigation Vol. 100; no. 2; pp. 339 - 349
• Main Authors: Muraro, P A, Vergelli, M, Kalbus, M, Banks, D E, Nagle, J W, Tranquill, L R, Nepom, G T, Biddison, W E, McFarland, H F, Martin, R
• Format: Journal Article
• Language: English
• Published: United States 15-07-1997
• Subjects: Adult; Amino Acid Sequence; Autoimmune Diseases - immunology; Binding, Competitive; CD4-Positive T-Lymphocytes - immunology; Cell Division; Coumarins - metabolism; Cytokines - secretion; Cytotoxicity Tests, Immunologic; DNA, Complementary; Female; HLA-DR Antigens - immunology; HLA-DR4 Antigen - genetics; HLA-DR4 Antigen - immunology; HLA-DRB1 Chains; Humans; Immunodominant Epitopes; Male; Middle Aged; Molecular Sequence Data; Multiple Sclerosis - immunology; Myelin Basic Protein - chemistry; Myelin Basic Protein - immunology; Myelin Basic Protein - metabolism; Peptide Fragments - immunology; Protein Binding; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology
• ISSN: 0021-9738
• DOI: 10.1172/JCI119539

The pathogenesis of multiple sclerosis (MS) is currently ascribed in part to a T cell-mediated process targeting myelin components. The T cell response to one candidate autoantigen, myelin basic protein (MBP), in the context of HLA-DR15Dw2, has been previously studied in detail. However, the characteristics of cellular immunity in the context of other MS-associated HLA-DR haplotypes are scarcely known. MBP-specific T cell lines (TCL) were generated from HLA-DR4 (B1*0401)-positive MS subjects. Out of 275 MBP-specific TCL, 178 (64. 7%) specifically recognized region MBP(111-129), predominantly in the context of DRB1*0401. The major T cell epitope for MBP recognition corresponded to residues MBP(116-123). These TCL expressed disparate profiles of cytokine secretion and cytotoxicity. T cell receptor analysis, on the other hand, revealed a strikingly limited heterogeneity of rearrangements. In contrast to MBP(81-99), which binds with high affinity to HLA-DR15 and is recognized by a diverse T cell repertoire, MBP(111-129) binds weakly to DRB1*0401, suggesting that only high affinity T cell receptors might be able to efficiently engage such unstable MHC/peptide complexes, thus accounting for the T cell receptor restriction we observed. This study provides new insight about MBP recognition and proposes an alternative mechanism for immunodominance of self-antigen T cell epitopes in humans.