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

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.