STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death

Abstract

STING gain-of-function mutations cause lung disease and T cell cytopenia through unknown mechanisms. Here, we found that these mutants induce chronic activation of ER stress and unfolded protein response (UPR), leading to T cell death by apoptosis in the <i>Sting^N153S/+</i> mouse and in human T cells. Mechanistically, STING-N154S disrupts calcium homeostasis in T cells, thus intrinsically primes T cells to become hyperresponsive to T cell receptor signaling-induced ER stress and the UPR, leading to cell death. This intrinsic priming effect is mediated through a novel region of STING that we name "the UPR motif," which is distinct from known domains required for type I IFN signaling. Pharmacological inhibition of ER stress prevented <i>Sting^N153S/+</i> T cell death in vivo. By crossing <i>Sting^N153S/+</i> to the <i>OT-1</i> mouse, we fully restored CD8⁺ T cells and drastically ameliorated STING-associated lung disease. Together, our data uncover a critical IFN-independent function of STING that regulates calcium homeostasis, ER stress, and T cell survival.