CCR2 limits inflammatory functions of CD8 TRM cells that impair recognition memory during recovery from WNV encephalitis

Central nervous system (CNS) resident memory CD8 T cells (T _RM ) that express IFN-γ contribute to neurodegenerative processes, including synapse loss, leading to memory impairments. Here, we show that CCR2 signalling in CD8 T _RM that persist within the hippocampus after recovery from CNS infection with West Nile virus (WNV) significantly prevents the development of memory impairments. Using CCR2-deficient mice, we determined that CCR2 expression is not essential for CNS T cell recruitment or virologic control during acute WNV infection. However, transcriptomic analyses of forebrain CCR2 ⁺ versus CCR2 ^- CD8 T _RM during WNV recovery reveal that CCR2 signalling significantly regulates hippocampal CD8 T _RM phenotype and function via extrinsic and intrinsic effects, decreasing the expression of CD103 and granzyme A and IFN-γ, respectively. Consistent with this, WNV-recovered Cd8a ^cre Ccr2 ^fl/fl mice exhibit decreased recognition memory. Our findings highlight a neuroprotective role for CCR2 in limiting CD8 T cell-mediated neuroinflammation and cognitive deficits, providing insights into potential therapeutic targets for CNS infections.