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

Abstract

BackgroundPrevious 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 (bTRM) following murine cytomegalovirus (MCMV) infection.MethodsFlow 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 bTRMs.ResultsIn 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 bTRM, and differences were observed in the numbers of these cells when compared to PD-L1 KOs. Immunohistochemical studies revealed that brain-resident CD103+ bTRM cells were localized to the parenchyma. Higher frequencies of CXCR3 were also observed among WT animals in contrast to PD-L1 KOs.ConclusionsTaken together, our results indicate that bTRMs 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0860-3) contains supplementary material, which is available to authorized users.

Reactive glia promote development of CD103+CD69+ CD8+ T‐cells through programmed cell death‐ligand 1 (PD‐L1)

“…Previous findings from our laboratory reported that CD103 þ CD69 þ CD8 þ T-cells persist within the brain of murine cytomegalovirus (MCMV)-infected animals. We also reported that PD-1: PD-L1 signaling altered expression CD103 and CD69 [10]. There is also evidence that PD-L1 expression on microglia regulates the differentiation of Th1 cells via nitric oxide, suggesting a role for these cells in regulating T-cells [2].…”

“…In our previous study, we used a well‐established mouse model of MCMV brain infection to demonstrate a role for the PD‐1: PD‐L1 pathway in development of CD103 + CD69 + CD8 + bT RM populations in vivo following acute viral infection . Here, we followed‐up on those findings by first demonstrating that some of the bT RM were specific for a previously identified viral T‐cell epitope .…”

“…Our laboratory and others have previously reported the early induction of CD69 expression on brain infiltrating effector T‐cells, as well as the local conversion of infiltrating CD8 + T‐cells to CD69 + CD103 + cells within MCMV‐infected brain . Other studies report that dendritic cell accumulation in skin epithelium and dermis can provide Ag and type I IFN for CD69 induction in T‐cells in vitro; however, Ag and type I IFN are dispensable for CD69 expression in vivo [17].…”

“…To provide protection against viral infection, tissueinfiltrating CD8 þ T-cells differentiate into several distinct subsets [9][10][11][12]. Tissue resident memory (T RM ) CD8 þ T-cells are one of these unique subsets that develop following resolution of primary infection to impart long-term immunity against re-infection [13][14][15].…”

Brain‐resident memory CD8+ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

“…Many additional signals are central in differentiation and survival of T RM cells, for example TGF-β, IL-15, TNF-α and IL-33 (Mackay et al, 2013, Skon et al, 2013). Upon intracerebral infection of adult mice the PD-1/PDL-1 pathway seems to contribute to the generation of CD8 + T RM cells (Prasad et al, 2017). It will be of interest to investigate whether and how these signals contribute to the establishment of T RM cells upon MCMV infection of newborn mice, especially taking into account the immaturity of the immune system, the developmental changes that occur simultaneously and disparate cytokine milieu in newborn mice as compared to adult animals.…”