Analysis of autoreactive T cells associated with murine collagen-induced arthritis using peptide-MHC multimers

Int Immunol. 2004 Feb;16(2):283-93. doi: 10.1093/intimm/dxh039.


CD4(+) T cells that recognize residues 256-270 of type II collagen (CII) associated with the I-A(q) (A(q)) molecule play a central role in disease pathogenesis in murine collagen-induced arthritis (CIA). Disease is most efficiently induced by immunization with heterologous CII, which elicits heterologous, e.g. bovine, CII256-270:I-A(q)-specific T cells that only poorly cross-react with mouse CII. The self-epitope differs from heterologous CII256-270 by a conservative change of glutamic acid (heterologous) to aspartic acid (mouse) at position 266 which confers a lower affinity for binding to the I-A(q) molecule. To date, characterization of the nature of T cell recognition in this model has been hindered by the lack of suitable, labeled multimeric peptide-MHC class II complexes. Here, we describe the biochemical properties of both recombinant bovine CII256-270:I-A(q) (bCII256-270:I-A(q)) and mouse CII256-270:I-A(q) (mCII256-270:I-A(q)) complexes, and use these as fluorescently labeled multimers (tetramers) to characterize the specificity of CII-reactive T cells. Our analyses show that an unexpectedly high percentage of bCII256-270:I-A(q)-specific T cells are cross-reactive with mCII256-270:I-A(q). Interestingly, one T cell clone which has a relatively high avidity for binding to self-CII256-270:I-A(q) shows a marked increase in binding avidity at physiological temperature, indicating that this TCR has unusual thermodynamic properties. Taken together, our analyses suggest that the low affinity of mCII256-270 for I-A(q) may lead to a state of ignorance which can be overcome by priming CII-specific T cells with heterologous CII. This has relevance to understanding the mechanism by which CIA is induced and provides an explanation for the low arthritogenicity of mouse CII.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigen Presentation / immunology
  • Arthritis, Experimental / immunology*
  • Autoimmunity / immunology
  • CD4 Antigens / immunology*
  • CD8 Antigens / immunology
  • Cattle
  • Collagen Type II / genetics
  • Collagen Type II / immunology*
  • Disease Models, Animal
  • Histocompatibility Antigens Class II / immunology*
  • Immune Tolerance / immunology
  • Immunization
  • Immunodominant Epitopes / immunology
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred DBA
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • T-Lymphocytes / immunology*


  • CD4 Antigens
  • CD8 Antigens
  • Collagen Type II
  • Histocompatibility Antigens Class II
  • Immunodominant Epitopes
  • Recombinant Proteins