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

J Clin Invest. 1997 Jul 15;100(2):339-49. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Autoimmune Diseases / immunology
  • Binding, Competitive
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Division
  • Coumarins / metabolism
  • Cytokines / metabolism
  • 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*


  • Coumarins
  • Cytokines
  • DNA, Complementary
  • HLA-DR Antigens
  • HLA-DR4 Antigen
  • HLA-DRB1 Chains
  • HLA-DRB1*04:01 antigen
  • Immunodominant Epitopes
  • Myelin Basic Protein
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • 7-amino-4-methylcoumarin-3-acetic acid