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Degenerate self-reactive human T-cell receptor causes spontaneous autoimmune disease in mice

Nature Medicine volume 10, pages 920926 (2004) | Download Citation

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Abstract

Thyroid autoimmune disorders comprise more than 30% of all organ-specific autoimmune diseases and are characterized by autoantibodies and infiltrating T cells. The pathologic role of infiltrating T cells is not well defined. To address this issue, we generated transgenic mice expressing a human T-cell receptor derived from the thyroid-infiltrating T cell of a patient with thyroiditis and specific for a cryptic thyroid-peroxidase epitope. Here we show that mouse major histocompatibility complex molecules sustain selection and activation of the transgenic T cells, as coexpression of histocompatibility leukocyte antigen molecules was not needed. Furthermore, the transgenic T cells had an activated phenotype in vivo, and mice spontaneously developed destructive thyroiditis with histological, clinical and hormonal signs comparable with human autoimmune hypothyroidism. These results highlight the pathogenic role of human T cells specific for cryptic self epitopes. This new 'humanized' model will provide a unique tool to investigate how human pathogenic self-reactive T cells initiate autoimmune diseases and to determine how autoimmunity can be modulated in vivo.

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Acknowledgements

We thank R. Reid and his staff for the animal facilities; B. Rapaport, R. Lechler and R. Germain for the cell lines; and B. Askonas and T. Elliott for discussions and critical reading of the manuscript. This work was supported by a Wellcome Trust Career Development Research Fellowship (S.Q.) and Cancer Research UK grant C7056/A31.

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Affiliations

  1. Cancer Research UK Oncology Unit, Cancer Sciences Division, University of Southampton, MP824, Southampton SO16 6YD, UK.

    • Sonia Quaratino
    • , Ester Badami
    •  & Yun Yun Pang
  2. MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road London, W12 0NN, UK.

    • Istvan Bartok
    •  & Julian Dyson
  3. Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

    • Dimitris Kioussis
  4. Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.

    • Marco Londei
    •  & Luigi Maiuri

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Sonia Quaratino.

Supplementary information

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  1. 1.

    Supplementary Fig. 1

    Peripheral expression of human TCRBV1.

  2. 2.

    Supplementary Table 1

    Cellularity in TAZ-10 transgenic mice.

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DOI

https://doi.org/10.1038/nm1092