Dynamic STING repression orchestrates immune cell development and function.

STING is an essential component of the innate immune system, yet homeostatic STING expression patterns and regulation are unknown. Using reporter and conditional transgenic mice, we found that regulation of STING expression is critical for immune cell development and functionality. STING expression was repressed in neutrophils, and forced STING expression or signaling drove systemic inflammatory disease. During T lymphocyte development, STING expression was restricted at the double-positive stage via epigenetic silencing by DNA methyltransferase 1. Forced STING expression or signaling impaired T lymphocyte development independent of type I interferon and promoted lineage commitment to innate-like γδ T cells over adaptive αβ T cells. In the tumor microenvironment, CD8 T lymphocytes repressed STING expression, correlating with features of T cell exhaustion in syngeneic mouse tumors and human colorectal cancer. Our data demonstrate the necessity of controlled, rather than ubiquitous, STING expression, uncovering a previously unappreciated dimension of STING pathobiology.