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.
Author Info: (1) Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX.
Author Info: (1) Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX. (2) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX. (3) Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX. (4) Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX. (5) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX. (6) Department of Medicine, Washington University School of Medicine, St. Louis, MO. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO. (7) Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX nan.yan@utsouthwestern.edu. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX.
