Mitochondrial antiviral signaling molecule-mediated mitochondrial calcium regulates CD8 T cell function during acute virus infection (VIR6P.1163)

MAVS is a crucial adaptor molecule through which RIG-I-like receptors (RLR)s signal to mediate downstream innate antiviral and inflammatory responses. However a role for MAVS in directly programming adaptive immunity has not been defined. Here we identified a cell-intrinsic role for MAVS in programming CD8 T cells following virus infection. We utilized a mouse model of acute Lymphocytic choriomeningitis virus (LCMV) infection to define the actions of adoptively transferred WT or MAVS deficient CD8 T cells. Lack of MAVS lead to defects in CD8 T cell expansion as well as function as measured by cytokine and cytotoxic T cell effector molecule production but these parameters were not deficient in double knockout mice lacking the RLRs MDA5 and RIG-I. We identified defects in total cytoplasmic calcium, mitochondrial calcium as well as mitochondrial membrane potential in MAVS-/- CD8 T cells in vivo . We found that the inflammatory conditions of LCMV -induced cell proliferation place a metabolic load on CD8 T cells and their mitochondria such that the absence of MAVS lead to defects in mitochondrial calcium independently of the RLRs. Importantly, the MAVS defect associated with defective nuclear factor of activated T cells c1 (NFATc1) activation and consequently decreased IL-2 production. Our study assigns a cell-intrinsic role for MAVS in regulating adaptive immunity following viral infection by means of regulating mitochondrial calcium and thereby affecting T cell fitness.