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

Huang, Jason C., Vestberg, Mikael, Minguela, Alfredo, Holmdahl, Rikard and Ward, E. Sally (2004) Analysis of autoreactive T cells associated with murine collagen-induced arthritis using peptide-MHC multimers. International Immunology, 16 (2), 283-293. (doi:10.1093/intimm/dxh039).

Abstract

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.

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Contributors

Author: E. Sally Ward

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