T cell response to myelin basic protein in the context of the multiple sclerosis-associated HLA-DR15 haplotype: Peptide binding, immunodominance and effector functions of T cells

M. Vergelli, M. Kalbus, S. C. Rojo, B. Hemmer, H. Kalbacher, L. Tranquill, H. Beck, H. F. McFarland, R. De Mars, E. O. Long, R. Martin

Research output: Contribution to journalArticlepeer-review

Abstract

In this study, we evaluated the role of the two functional HLA-DR heterodimers, DR2a (DR α paired with the β chain encoded by DRB5(*) 0101) and DR2b (DR α paired with the β chain encoded by DRB1(*)1501), that are coexpressed in the multiple sclerosis (MS)-associated haplotype HLA-DR15 Dw2, in presenting myelin basic protein (MBP) peptides to MBP-specific T cell lines (TCL). Our results show that both HLA-DR molecules serve as restriction elements for HLA-DR15-restricted TCL. Slightly higher numbers of TCL use DR2a as restriction element, and the epitopes contained in the immunodominant C-terminal region (131-159) are uniquely restricted by DR2a. The immunodominant middle epitope (81-99) is recognized in the context of both DR2a and DR2b, but this specificity strongly dominates the DR2b-restricted T cell response. Overall, immunodominance in the MBP-specific T cell response correlated well with peptide binding to DR2a or DR2b, demonstrating that the affinity of MHC-peptide interactions is important for shaping the T cell response to this autoantigen. Furthermore, we show that binding of the middle MBP peptide to HLA-DR15 molecules prevents cleavage by cathepsin D, a protease abundantly found in endosomal processing compartments, and thus contributes to its immunodominance. Surprisingly, the restriction element employed by MBP-specific T cell clones influenced the effector function (i.e., cytotoxic activity) of T cells irrespective of their peptide fine specificity.

Original languageEnglish (US)
Pages (from-to)195-203
Number of pages9
JournalJournal of Neuroimmunology
Volume77
Issue number2
DOIs
StatePublished - Aug 1997
Externally publishedYes

Keywords

  • HLA binding
  • HLA-DR15
  • Immunodominance
  • MBP
  • Multiple sclerosis

ASJC Scopus subject areas

  • Immunology
  • Clinical Neurology
  • Immunology and Allergy
  • Neurology

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