Tolerance and immunity to the inducible self antigen C-reactive protein in transgenic mice

Authors

  • Thomas C. Klein,

    1. Tumor Immunology Programme, Division of Cellular Immunology, German Cancer Research Centre, Heidelberg, Germany
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  • Rainer Döffinger,

    1. Tumor Immunology Programme, Division of Cellular Immunology, German Cancer Research Centre, Heidelberg, Germany
    Current affiliation:
    1. Tuberculosis and Related Infections Unit, MRC-Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W120NN, GB
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  • Mark B. Pepys,

    1. Immunological Medicine Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, GB
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  • Ulrich Rüther,

    1. Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
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  • Bruno Kyewski

    Corresponding author
    1. Tumor Immunology Programme, Division of Cellular Immunology, German Cancer Research Centre, Heidelberg, Germany
    • Tumor Immunology Programme, Division of Cellular Immunology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany (Fax: 49 6221 423702)
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Abstract

The understanding of immunological tolerance has been greatly aided by the development of transgenic animal models in which expression of a specific T cell receptor (or B cell receptor) and its cognate self antigen is experimentally controlled. In most cases, expression of the self antigen was constitutive and did not allow for variation of its time- and dose-dependent expression pattern, parameters which are known to influence the balance of tolerance versus immunity. We describe a transgenic model in which expression of human C-reactive protein (hCRP), an acute-phase protein, is tightly controlled at basal levels (female mice express around 10−9 M and male mice 5 × 10−7 M circulating hCRP) and is highly inducible (induction factor of 25–500). T cells from C57BL/6 mice recognize two epitopes of hCRP termed A (residues 79–95) and B (residues 87–102). Different efficacies of presentation in vitro and in vivo identify epitope A as subdominant and epitope B as dominant. T cells of non-induced hCRP transgenic mice are tolerant to the dominant epitope, but reactive to the subdominant epitope. A hCRP-specific IgG antibody response is detectable in transgenic mice, but is weaker than in littermates. Upon induction of hCRP, both T cell epitopes are presented by thymic and splenic antigen-presenting cells (APC) in vivo. Kinetics of presentation by splenic APC closely match serum kinetics of hCRP, whereas presentation in the thymus is considerably prolonged. This model enables epitope-specific T cell tolerance to be studied as a function of time- and dose-dependent expression of the self antigen.

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