Differential expression of tissue-restricted antigens among mTEC is associated with distinct autoreactive T cell fates

Marie-Ève Lebel, Marie Coutelier, Maria Galipeau, Claudia L. Kleinman, James J. Moon and Heather J. Melichar ()
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Marie-Ève Lebel: Maisonneuve-Rosemont Hospital Research Center
Marie Coutelier: The Lady Davis Institute for Medical Research, Jewish General Hospital
Maria Galipeau: Maisonneuve-Rosemont Hospital Research Center
Claudia L. Kleinman: The Lady Davis Institute for Medical Research, Jewish General Hospital
James J. Moon: Center for Immunology and Inflammatory Diseases and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School
Heather J. Melichar: Maisonneuve-Rosemont Hospital Research Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Medullary thymic epithelial cells (mTEC) contribute to the development of T cell tolerance by expressing and presenting tissue-restricted antigens (TRA), so that developing T cells can assess the self-reactivity of their antigen receptors prior to leaving the thymus. mTEC are a heterogeneous population of cells that differentially express TRA. Whether mTEC subsets induce distinct autoreactive T cell fates remains unclear. Here, we establish bacterial artificial chromosome (BAC)-transgenic mouse lines with biased mTEClo or mTEChi expression of model antigens. The transgenic lines support negative selection of antigen-specific thymocytes depending on antigen dose. However, model antigen expression predominantly by mTEClo supports TCRαβ+ CD8αα intraepithelial lymphocyte development; meanwhile, mTEChi-restricted expression preferentially induces Treg differentiation of antigen-specific cells in these models to impact control of infectious agents and tumor growth. In summary, our data suggest that mTEC subsets may have a function in directing distinct mechanisms of T cell tolerance.

Date: 2020
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DOI: 10.1038/s41467-020-17544-3

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