title: Analysis of autoreactive T cells associated with murine collagen-induced arthritis using peptide-MHC multimers.
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.
authors.affiliation: Center for Immunology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390-9093, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Huang
authors.forename: Mikael
authors.initials: M
authors.lastname: Vestberg
authors.forename: Alfredo
authors.initials: A
authors.lastname: Minguela
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: E Sally
authors.initials: ES
authors.lastname: Ward
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D002417:Cattle; D024043:Collagen Type II / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D024043:Collagen Type II; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D011994:Recombinant Proteins