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

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Abstract

Coatomer protein complex subunit α (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 stimulator of interferon genes (STING) is centrally involved in disease. However, the mechanisms by which STING results in autoimmunity are not well understood in COPA syndrome and other STING-associated diseases. Prior studies showed a cell autonomous role for STING in thymocyte development. Single-cell data of human thymus demonstrated that STING is highly expressed in medullary thymic epithelial cells (mTECs) and at levels much greater than in 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 CopaE241K/+ mice, activated STING in mTECs amplified IFN signaling, impaired macroautophagy, and caused a defect in negative selection of T cell precursors. WT 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 that STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings that are important for conditions that activate thymic STING.

Authors

Zimu Deng, Christopher S. Law, Santosh Kurra, Noa Simchoni, Anthony K. Shum