CD8+ T cell intrinsic MAVS promotes antigen-specific responses and mitochondrial metabolism during West Nile Virus neuroinvasive disease

Abstract

Abstract West Nile Virus (WNV) is an arbovirus of the Flaviviridae family that causes annual outbreaks of encephalitis across North America. RIG-I like receptor (RLR) signaling through the central adaptor Mitochondrial antiviral signaling protein (MAVS) is essential for promoting immunity against WNV infection. While MAVS has been associated with type I interferon (IFN) induction during virus infection, here we describe a novel, cell-intrinsic role for MAVS in regulating antigen-specific CD8+ T cell responses. MAVS is expressed in CD8+ T cells and remains constant during the differentiation of CD8+ T cells. Generation of an effective CD8+ T cell response against WNV is essential for limiting virus replication in neurons, mitigating pathology in the brain, and protecting against lethal outcome. To understand how MAVS impacts CD8+ T cell responses during WNV infection, we utilized the WNV mouse model and adoptively co-transferred WT and Mavs−/− CD8+ T cells into congenically marked WT mice. We found that compared to WT cells, Mavs−/− antigen-specific CD8+ T cells displayed reduced accumulation of antigen-specific CD8+ T cells, reduced IFN-γ production and reduced formation of memory precursor cells during virus infection. At the peak of brain infection, Mavs−/− antigen-specific CD8+ T cells displayed highly divergent transcriptomes, including altered metabolic profiles, compared to WT CD8+ T cells. Further mechanistic studies found that after TCR stimulation of CD8+ T cells, MAVS promotes oxidative respiration and remodeling of mitochondrial morphology. Our findings identify a novel, non-canonical role for MAVS in the regulation of antigen-specific CD8+ T cell responses and mitochondrial function during neuroinvasive viral infection.