Dynamic STING repression orchestrates immune cell functionality across development and maturation.

Stimulator of Interferon Genes (STING) is a critical component of the innate immune system. Mechanisms of STING-mediated type I interferon (IFN-I) signaling during infection are well studied in myeloid cells. However, homeostatic STING expression patterns and their regulation, particularly in lymphoid cells, are unknown. We established a Sting1IRES-EGFP reporter mouse to systematically characterize STING expression spatially in tissues and temporally along development of immune cells. Using this reporter and conditional Sting1 transgenic mouse models, we show that STING expression is repressed in neutrophils and forced STING signaling and expression drives systemic inflammatory disease due to secretion of cytokines and chemokines by neutrophils. Additionally, we show that STING expression is temporally restricted during T lymphocyte development at the double positive stage. Forced STING expression and signaling severely impairs T lymphocyte development and reduces thymopoiesis independent of the type I IFN receptor (IFNAR1). Mechanistically, STING expression in the thymus is controlled via epigenetic silencing by DNA methyltransferase 1 (DNMT1). Forced STING signaling in the thymus favors lineage commitment to innate-like gd T cells rather than adaptive ab T cells, revealing a previously unanticipated role of STING in T lymphocyte fate choice. Using two syngeneic tumor models and a cohort of human colorectal cancer patients, we found that tumor-infiltrating CD8+ T lymphocytes gradually repress STING expression as a tumor grows and loss of STING expression strongly correlates with CD8+ T cell exhaustion. Together, our data demonstrates the physiological importance of controlled, rather than ubiquitous STING expression and uncovers STING expression dynamics as an important new dimension of STING pathobiology.