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

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.