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

Paolo A. Muraro, Marco Vergelli, Matthias Kalbus, Darhlene E. Banks, James W. Nagle, Laura R. Tranquill, Gerald T. Nepom, William E. Biddison, Henry F. McFarland, Roland Martin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)339-349
Number of pages11
JournalJournal of Clinical Investigation
Volume100
Issue number2
StatePublished - Jul 15 1997
Externally publishedYes

Keywords

  • Autoantigens
  • Autoimmune diseases
  • CD4-positive T lymphocytes
  • Complementarity-determining region
  • Multiple sclerosis

ASJC Scopus subject areas

  • Medicine(all)

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