Activated STING in the thymic epithelium alters T cell development and selection leading to autoimmunity

COPA syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Constitutive activation of the innate immune molecule STING is centrally involved in disease. However, the mechanisms by which STING results in autoimmunity is not well understood in COPA syndrome and other STING-associated diseases. Prior studies show a cell autonomous role for STING in thymocyte development. Single cell data of human thymus demonstrates STING is highly expressed in medullary thymic epithelial cells (mTECs) and at levels much greater than T cells. Here, we show that in certain contexts activated STING exerts a functional role in the thymic epithelium to alter thymocyte selection and predisposes to autoimmunity. In Copa^E241K/+ mice, activated STING in mTECs amplified interferon signaling, impaired macroautophagy and caused a defect in negative selection of T cell precursors. Wild-type mice given a systemic STING agonist phenocopied the selection defect and showed enhanced thymic escape of a T cell clone targeting a self-antigen also expressed in melanoma. Our work demonstrates STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings important for conditions that activate thymic STING.

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