The PD-1: PD-L1 pathway promotes development of brain-resident memory T cells following acute viral encephalitis

Background: Previous work from our laboratory has demonstrated that during acute viral brain infection, glial cells modulate antiviral T cell effector responses through the PD-1: PD-L1 pathway, thereby limiting the deleterious consequences of unrestrained neuroinflammation. Here, we evaluated the PD-1: PD-L1 pathway in development of brain-resident memory T cells (bT_RM) following murine cytomegalovirus (MCMV) infection. Methods: Flow cytometric analysis of immune cells was performed at 7, 14, and 30 days post-infection (dpi) to assess the shift of brain-infiltrating CD8⁺ T cell populations from short-lived effector cells (SLEC) to memory precursor effector cells (MPEC), as well as generation of bT_RMs. Results: In wild-type (WT) animals, we observed a switch in the phenotype of brain-infiltrating CD8⁺ T cell populations from KLRG1⁺ CD127^- (SLEC) to KLRG1^- CD127⁺ (MPEC) during transition from acute through chronic phases of infection. At 14 and 30 dpi, the majority of CD8⁺ T cells expressed CD127, a marker of memory cells. In contrast, fewer CD8⁺ T cells expressed CD127 within brains of infected, PD-L1 knockout (KO) animals. Notably, in WT mice, a large population of CD8⁺ T cells was phenotyped as CD103⁺ CD69⁺, markers of bT_RM, and differences were observed in the numbers of these cells when compared to PD-L1 KOs. Immunohistochemical studies revealed that brain-resident CD103⁺ bT_RM cells were localized to the parenchyma. Higher frequencies of CXCR3 were also observed among WT animals in contrast to PD-L1 KOs. Conclusions: Taken together, our results indicate that bT_RMs are present within the CNS following viral infection and the PD-1: PD-L1 pathway plays a role in the generation of this brain-resident population.