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

J Neuroimmunol. 1997 Aug;77(2):195-203. doi: 10.1016/s0165-5728(97)00075-1.


In this study, we evaluated the role of the two functional HLA-DR heterodimers, DR2a (DR alpha paired with the beta chain encoded by DRB5*0101) and DR2b (DR alpha paired with the beta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Cathepsin D / metabolism
  • Cell Line
  • Clone Cells
  • Cytotoxicity, Immunologic*
  • HLA-DR Antigens / genetics*
  • HLA-DR Antigens / metabolism
  • HLA-DR Serological Subtypes
  • HLA-DR2 Antigen / genetics
  • HLA-DR2 Antigen / metabolism
  • Haplotypes / immunology*
  • Humans
  • Hydrolysis
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / immunology*
  • Molecular Sequence Data
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Myelin Basic Protein / immunology*
  • Myelin Basic Protein / metabolism
  • Peptides / immunology*
  • Peptides / metabolism
  • Protein Binding / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Cytotoxic / immunology


  • HLA-DR Antigens
  • HLA-DR Serological Subtypes
  • HLA-DR15 antigen
  • HLA-DR2 Antigen
  • Immunodominant Epitopes
  • Myelin Basic Protein
  • Peptides
  • Cathepsin D