Hassani, Asma

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 Skull bone marrow (BM) is a recently identified site for immune activation responsive to CNS insults. The extent to which adaptive immunity is generated through skull BM is poorly understood. In this study, we evaluated how skull BM supports the early expansion of antiviral CD8 T cells during acute neurotropic virus infection. Virus antigen-specific CD8 T cells were rapidly identified in skull BM at a rate comparable to lymphoid compartments during acute Theiler’s murine encephalomyelitis viral (TMEV) infection. We therefore employed MHC class I conditional knockout mice and demonstrated the necessity of CD11c+ antigen-presenting cells (APCs) for the generation of various subsets of TMEV-specific CD8 T cells in skull BM. Importantly, the early expansion of skull BM-derived antiviral T cells was impeded by FTY720 treatment and restored upon shared circulation with a mouse exhibiting intact antigen presentation by CD11c+ APCs. Additionally, TMEV-specific CD8 T cells were retained in skull BM during both chronic CNS infection and long after infection has been resolved. Overall, we determined that skull BM responds to acute neurotropic viral infection through the rapid recruitment of virus-specific CD8 T cells primed in the periphery before serving as a reservoir for immunologic memory.