Witter, Ryann K

Abstract The impact of microglia antigen presentation on CNS infiltrating CD8 T cells responses during neurotropic virus infection remains undefined. Using Theiler’s murine encephalomyelitis virus (TMEV) infection of neurons as a model system, we generated H-2K b and H-2D b Tmem119 conditional knockout mice. During TMEV infection, we determined using Tmem119 K b cKO mice that microglia H-2K b contributes to antiviral CD8 T cell proliferation in the brain. Meanwhile, using Tmem119 D b cKO mice we determined that microglia H-2D b increased antiviral CD8 T cell perforin levels and the capacity to induce blood-brain barrier (BBB) disruption. Furthermore, microglial H-2D b was essential for antigen-specific reactivation of CD8 tissue resident memory (TRM) cell recall responses and BBB disruption long after virus had been cleared. These findings demonstrate discrete roles of individual MHC class I genes on microglia in CD8 T cell proliferation, effector functions, memory recall and neuropathology.

Abstract The impact of microglia antigen presentation on CNS infiltrating CD8 T cells responses during neurotropic virus infection has been difficult to define. Using Theiler’s murine encephalomyelitis virus (TMEV) infection of neurons as a model system, our laboratory has previously determined that H-2D b restricted, but not H-2K b restricted CD8 T cells are required for viral clearance, demonstrating the role of discrete MHC class I alleles. To determine the extent microglia antigen presentation impacts brain-infiltrating CD8 T cells, our laboratory generated novel single MHC class I conditional knockout mice in which H-2K b or H-2D b can be specifically deactivated in TMEM119+ microglia with tamoxifen administration. During TMEV infection, conditional knockout of H-2K b in microglia reduced antigen-specific CD8 T cell proliferation in the brain. Meanwhile, mice with deletion of D b in microglia had reduced levels of perforin in antigen-specific CD8 T cells. Furthermore, microglia specific deletion of H-2D b reduced CD8 T cell numbers in the brain and preserved blood-brain barrier (BBB) integrity. Microglial D b restricted antigen presentation was also essential for the reactivation of CD8 tissue resident memory (TRM) cells and BBB integrity during memory recall responses. These findings further our understanding of how brain infiltrating antiviral CD8 T cell responses are impacted by microglia, as well as define how this cellular interaction contributes to BBB disruption during neuroinflammation. These findings also have high significance to our understanding of how microglia impact CD8 TRM cell populations that reside in the brain long after virus infection is cleared. Graphical abstract