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.
Highlights
Medullary thymic epithelial cells 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
The frequency of major histocompatibility complex (MHC) class II+ cells expressing a given TRA in the thymus correlates with the mechanism of CD4+ T cell tolerance; it has been suggested that high numbers of cells expressing self-antigen drive clonal deletion whereas lower levels of thymic antigen presentation predominantly leads to nondeletional tolerance mechanisms and regulatory T cell (Treg) generation[8]
Expression of a model antigen is directed from either the C-reactive protein (Crp) locus, whose autoimmune regulator (Aire)-independent expression is preferentially detected among immature mTEClo, or the Insulin[2] (Ins2) locus, where expression is restricted to Aire+ mTEChi (Supplementary Fig. 1a, b12,21)
Summary
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. 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. The mTEClo (CD80/CD86lo MHC class IIlo) compartment includes “immature” progenitor cells, as well as a functionally mature subset and a population of terminally differentiated epithelial cells[12,13,17]. As they differentiate, immature mTEClo upregulate co-stimulatory molecule expression and MHC class II levels to become mTEChi. This is relevant to the design of therapeutic approaches that aim to modulate the function of self-reactive T cells
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