T cell tolerance and activation to a transgene-encoded tumor antigen

Authors

  • Antony Antoniou,

    1. Transplantation Biology Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, GB
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  • David McCormick,

    1. Transplantation Biology Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, GB
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  • Diane Scott,

    1. Transplantation Biology Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, GB
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  • Helen Yeoman,

    1. Division of Molecular Immunology, National Institute for Medical Research, London, GB
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  • Phillip Chandler,

    1. Transplantation Biology Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, GB
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  • Andrew Mellor,

    1. Division of Molecular Immunology, National Institute for Medical Research, London, GB
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  • Julian Dyson

    Corresponding author
    1. Transplantation Biology Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, GB
    Current affiliation:
    1. Department of Biochemistry, Medical sciences Institute, University of Dundee, Dundee, GB
    • Transplantation Biology Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Rd, London W12 ONN, GB (Fax: +44181-259-8303)
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Abstract

Much has been learned in recent years concerning the nature of tumor antigens recognized by T cells. To apply this knowledge clinically, the nature of the host response to individual and multiple tumor antigens has to be characterized. This will help to define the efficacy of immune surveillance and the immune status of the host following exposure to tumor antigens expressed on pre-neoplastic tissue. To approach these questions, we have developed a transgenic mouse which expresses the tumor-specific antigen P91A. The single amino acid substitution in P91A results in the expression of a new MHC class I (H-2Ld)-binding peptide. In transgenic tissue, the H-2Ld/P91A complex is expressed in isolation from other tumor-associated antigens, allowing definition of the immune response to a single defined tumor antigen, a situation closely analogous to events during tumorigenesis. We show that CD8+ T cell immune surveillance of P91A is ineffective without the introduction of a helper determinant operating through stimulation of CD4+ T cells. Recognition of the isolated P91A tumor antigen on normal tissue by CD8+ T cells is a tolerogenic process. Induction of T cell tolerance suggests tumor antigen-T cell interactions occurring during tumorigenesis may elicit T cell tolerance and hence confound some immunotherapeutic approaches.

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