title: Immunodominance of a low-affinity major histocompatibility complex-binding myelin basic protein epitope (residues 111-129) in HLA-DR4 (B1*0401) subjects is associated with a restricted T cell receptor repertoire.
abstract: 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.
authors.affiliation: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1400, USA. pmuraro@box-p.nih.gov
authors.forename: P A
authors.initials: PA
authors.lastname: Muraro
authors.forename: M
authors.initials: M
authors.lastname: Vergelli
authors.forename: M
authors.initials: M
authors.lastname: Kalbus
authors.forename: D E
authors.initials: DE
authors.lastname: Banks
authors.forename: J W
authors.initials: JW
authors.lastname: Nagle
authors.forename: L R
authors.initials: LR
authors.lastname: Tranquill
authors.forename: G T
authors.initials: GT
authors.lastname: Nepom
authors.forename: W E
authors.initials: WE
authors.lastname: Biddison
authors.forename: H F
authors.initials: HF
authors.lastname: McFarland
authors.forename: R
authors.initials: R
authors.lastname: Martin
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000276:immunology; D001667:Binding, Competitive; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D003374:Coumarins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D018076:DNA, Complementary; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D016056:Immunodominant Epitopes; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology*; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*
chemical_list: D003374:Coumarins; D016207:Cytokines; D018076:DNA, Complementary; D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C051029:7-amino-4-methylcoumarin-3-acetic acid