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

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 mTEC^lo or mTEC^hi expression of model antigens. The transgenic lines support negative selection of antigen-specific thymocytes depending on antigen dose. However, model antigen expression predominantly by mTEC^lo supports TCRαβ⁺ CD8αα intraepithelial lymphocyte development; meanwhile, mTEC^hi-restricted expression preferentially induces T_reg 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.

SUBMITTER: Lebel ME

PROVIDER: S-EPMC7381629 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tissue restricted antigen expression by medullary thymic epithelial cell subsets induces distinct autoreactive T cell fates

Project description:Cellular interactions in the thymus play an essential role in ensuring the development of a self-tolerant T cell repertoire. Medullary thymic epithelial cells (mTECs) contribute to 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. This has largely been studied in the context of autoimmune regulator (Aire) dependent TRA expression in mature mTECs. Yet, mTECs are a heterogeneous population of cells that differentially express unique pools of TRA, and whether mTEC subsets induce distinct autoreactive T cell fates remains unclear. Here we attribute unique roles for mTEC subsets in directing distinct mechanisms of T cell tolerance that significantly impact infection and tumor control. These results have important implications in the design of effective therapeutic approaches that aim to modulate the function of self-reactive T cells.

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Tissue restricted antigen expression by medullary thymic epithelial cell subsets induces distinct autoreactive T cell fates

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