STING-mediated chronic activation of ER stress through disrupting calcium homeostasis primes T cells for cell death

Abstract STING is a central protein for innate immune response to a wide range of microbial pathogens. Gain-of-function STING mutations cause systemic inflammation, lung disease and T cell cytopenia in humans and in mice, although the mechanism of disease is not known. Here, we found that SAVI mutation N154S induces chronic activation of ER stress and unfolded protein response (UPR), leading to spontaneous T cell death by apoptosis in the Sting N153S/+ mouse and in human T cells. Mechanistically, we found that N154S severely disrupts calcium homeostasis in T cells, thus intrinsically primes T cells to become hyper-responsive to T cell receptor (TCR) signaling-induced ER stress and the UPR, leading to cell death. This intrinsic priming effect is mediated through a novel region of STING protein that we name ‘the UPR motif’, which is distinct from known domains required for interferon signaling. Point mutations that disrupt the UPR motif rescue N154S-mediated calcium dysregulation and ER stress, and blocks T cell death. Pharmacological inhibition of ER stress also prevented T cell death in vitro and in vivo. Furthermore, restoring only the CD8+ T cells rescued splenomegaly, hypercytokinmia and perivascular lung inflammation in the Sting N153S/+ mouse. Collectively, our data uncovers a critical IFN-independent function of STING that regulates calcium homeostasis, ER stress and T cell survival.