Acute and chronic viral infection generate brain-resident memory T cells with distinct phenotypic, functional, spatial, and metabolic profiles

Abstract The rising incidence of post-viral neurological sequelae represents a substantial burden on global public health. Therefore, there is an urgent need to investigate alterations in brain immune composition after acute and chronic viral infection. While virus-specific tissue-resident memory (T RM) CD8 +T cells are observed in human health and neurological disease, these populations remain understudied in the brain. Here, we leveraged the comparative model system of lymphocytic choriomeningitis virus (LCMV) strain Armstrong vs. Clone 13 infection in mice to generate brain T RMwith quiescent and exhausted profiles respectively. We then interrogated the 1) phenotype, 2) functionality, 3) localization, and 4) metabolism of anti-viral T RMin the brain. Importantly, brain T RMexhibit higher expression of exhaustion markers (PD-1, LAG-3, TIM-3, TOX) compared to T circulating memory (T CIRCM) cells in the same host. Furthermore, brain T RMin chronically infected hosts are functionally impaired in cytokine production and cytolytic capacity. Anti-viral brain T RMseed distinct neuroanatomical sites, such as the cerebrospinal fluid, parenchyma, and choroid plexus, often adopting aggregate-like structures in solid compartments. Compared to T CIRCM, quiescent and exhausted brain T RMalso demonstrate higher expression of surface amino acid transporters with disparate amino acid uptake. These findings are contextualized by whole brain metabolomic profiling indicating global perturbations in amino acid metabolism post-acute and chronic viral infection. Altogether, these data highlight brain-intrinsic memory T cell signatures and offer broad insight into how brain T RMmay influence post-viral neurological outcomes. Supported by grants from the NIH (AI042767, AI114543, AI167847, 5T32GM007337) and the University of Iowa Post-Comprehensive Research Fellowship.