Wu et al. elucidate the mechanisms underlying T cell death in the context of gain-of-function STING mutation (STINGN153S/+). STINGN153S/+ mice had reduced numbers of T cells, which displayed elevated apoptosis and unfolded protein response (UPR) and died following CD3/CD28 stimulation ex vivo, a phenomenon associated with aberrant STING localization and ER calcium signaling. A “UPR motif” identified in the cGAMP-binding domain of STING was found to be essential for UPR induction and NFκB signaling following TCR activation, linking chronic STING activation, UPR, and calcium homeostasis in TCR stimulation-mediated T cell death.
Contributed by Alex Najibi
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 Sting(N153S/+) 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 Sting(N153S/+) T cell death in vivo. By crossing Sting(N153S/+) to the OT-1 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.