Jin, Fang

Abstract Description The dura mater of the meninges recruits immune cells for CNS surveillance and response to infections, serving as a critical interface between the brain and the peripheral immune system. Theiler’s murine encephalomyelitis virus (TMEV) infection is a model neurotropic virus for which MHC class I molecules are critical for sterilizing immunity. Using spectral flow cytometry, we profiled the immune response in the dura mater in healthy and TMEV-infected wildtype mice. Acute TMEV infection resulted in the infiltration of diverse immune cell types into the dura mater, including increased cDC1, pDCs, monocytes, NK cells, CD4 T cells, and CD8 T cells. We next examined the importance of MHC class I molecules on diverse immune cell populations in the dura mater during acute TMEV infection. MHC class I deficiency resulted in increased numbers of CD4 T cells with high expression of PD1 in MHC class I-/- (H-2Kb-/-, H-2Db-/-) mice compared to WT mice 7 days post TMEV infection. This demonstrated the importance of MHC class I and CD8 T cells in modulating dura immune cell populations and implies a compensatory shift toward a CD4 T cell response during acute infection. Subsequent studies employing in vivo cell-specific ablation of MHC class I molecules in discrete cell types will further define the impact of antigen presentation on immune regulation and inflammatory outcomes within the dura mater. Topic Categories Neuroimmunology (NEUR)

Abstract Blood–brain barrier (BBB) disruption is a common feature of numerous neurologic disorders. A fundamental question in these diseases is the extent inflammatory immune cells contribute to CNS vascular permeability. We have previously shown that CD8 T cells play a critical role in initiating BBB disruption in the peptide-induced fatal syndrome model developed by our laboratory. However, myelomonocytic cells such as neutrophils have also been implicated in promoting CNS vascular permeability and functional deficit in murine models of neuroinflammatory disease. For this reason, we evaluated neutrophil depletion in a murine model of CD8 T cell-initiated BBB disruption by employing traditionally used anti-granulocyte receptor-1 mAb RB6-8C5 and Ly-6G–specific mAb 1A8. We report that CNS-infiltrating antiviral CD8 T cells express high levels of granulocyte receptor-1 protein and are depleted by treatment with RB6-8C5. Mice treated with RB6-8C5, but not 1A8, display: 1) intact BBB tight junction proteins; 2) reduced CNS vascular permeability visible by gadolinium-enhanced T1-weighted magnetic resonance imaging; and 3) preservation of motor function. These studies demonstrate that traditional methods of neutrophil depletion with RB6-8C5 are broadly immune ablating. Our data also provide evidence that CD8 T cells initiate disruption of BBB tight junction proteins and CNS vascular permeability in the absence of neutrophil support.