Antigen presentation by CNS-resident microglia and macrophages regulates CD8 T cell infiltration of the brain during central nervous system (CNS) infection

Abstract

Abstract CD8 T cell responses are essential for clearance of infections in the CNS but contribute to neuropathology. T cell interaction with antigen presenting cells (APCs) at CNS barriers is thought to allow activated antigen-specific T cells to infiltrate the CNS during neuroinflammation. However, the role of CNS-resident APCs during CD8 T cell infiltration of the CNS is unclear. To address this, we utilized Theiler’s murine encephalomyelitis virus (TMEV) and Plasmodium berghei ANKA (PbA) to assess the role of APCs during CD8 T cell responses to CNS infection in mice. During infection, we observed robust upregulation of MHC class I on microglia and brain associated macrophages (BAM). Microglia and BAMs were located in close proximity to inflamed vasculature where antigen presentation to T cells could occur. Thus, we hypothesized that microglia and BAMs are critical APCs for CNS infiltration of antigen specific CD8 T cells. To test this, we generated mice with inducible deletion of MHC class I on microglia and BAMs by crossing CX3CR1creERT2 mice with H-2Db or H-2Kb floxed mice (Db cKO or Kb cKO). We found that brain infiltrating virus-specific CD8 T cells were reduced in Db cKO mice compared to controls during TMEV infection, while peripheral priming of T cells was unaffected. Conversely, antigen-specific CD8 T cell infiltration was not impacted in Kb cKO mice infected with TMEV-OVA257–264. In Db cKO mice, brain-infiltrating CD8 T cells were increased during PbA induced experimental cerebral malaria (ECM), indicating a potential inhibitory role for CNS APCs. These results demonstrate that local antigen presentation by microglia/BAMs can both positively and negatively regulate CD8 T cell infiltration of the brain in discrete neurologic disease models.