Glial cells suppress postencephalitic CD8⁺ T lymphocytes through PD‐L1

Abstract

Engagement of the programmed death (PD)-1 receptor on activated cells by its ligand (PD-L1) is a mechanism for suppression of activated T-lymphocytes. Microglia, the resident inflammatory cells of the brain, are important for pathogen detection and initiation of innate immunity, however, a novel role for these cells as immune regulators has also emerged. PD-L1 on microglia has been shown to negatively regulate T-cell activation in models of multiple sclerosis and acute viral encephalitis. In this study, we investigated the role of glial cell PD-L1 in controlling encephalitogenic CD8+ T-lymphocytes, which infiltrate the brain to manage viral infection, but remain to produce chronic neuroinflammation. Using a model of chronic neuroinflammation following murine cytomegalovirus (MCMV)-induced encephalitis, we found that CD8+ T-cells persisting within the brain expressed PD-1. Conversely, activated microglia expressed PD-L1. In vitro, primary murine microglia, which express low basal levels of PD-L1, upregulated the co-inhibitory ligand upon IFN-γ-treatment. Blockade of the PD-1: PD-L1 pathway in microglial: CD8+ T-cell co-cultures increased T-cell IFN-γ and interleukin (IL)-2 production. We observed a similar phenomenon following blockade of this co-inhibitory pathway in astrocyte: CD8+ T-cell co-cultures. Using ex vivo cultures of brain leukocytes, including microglia and CD8+ T-cells, obtained from mice with MCMV-induced chronic neuroinflammation, we found that neutralization of either PD-1 or PD-L1 increased IFN-γ production from virus-specific CD8+ T-cells stimulated with MCMV IE1168-176 peptide. These data demonstrate that microglia and astrocytes control antiviral T-cell responses and suggest a therapeutic potential of PD1: PD-L1 modulation to manage the deleterious consequences of uncontrolled neuroinflammation.

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

“…One possible role of brain-resident memory CD4 + T cells could be to prevent tissue damage during virus reactivation, as is the case with T reg cells during acute intracranial MCMV infection of adult mice (Prasad et al, 2015). Indeed, many mechanisms are involved in regulation of CNS inflammation including expression of inhibitory receptors TIGIT and PD-1 on immune cells, or release of cytokines IL-10 and TGF-β (Ellwardt et al, 2016, Schachtele et al, 2014). It will be of interest to determine which mechanisms attenuate the potent immune response in brain of mice infected perinatally with MCMV.…”

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

“…In vitro studies from our laboratory demonstrated that both microglia and astrocytes upregulated MHC I and II, as well as PD‐L1 in response to IFN‐γ produced by anti‐CD3 Ab‐stimulated CD8 + T‐cells. It is well‐established that microglia possess a number of mechanisms to limit CNS inflammation and regulate immune responses in various disease settings . In this study, we identified the role of glial cells to promote the development of bT RM cells.…”

“…It has been reported that treating T RM cells with PD‐L1 blocking Abs results in increased cytokine production . Our previous data report that blockade of the PD‐1: PD‐L1 pathway in both microglia and astrocyte: CD8 T‐cell co‐cultures resulted in increased IFN‐γ and IL‐2 production . However, here we first gated for tetramer‐specific CD103+ CD8+ T‐cells from WT and PD‐L1 KO animals at 30 dpi; and then looked for IFN‐γ production by only the tetramer‐specific bTRM cells during recall responses (i.e., not the total CD8+ T‐cell response).…”

Immune Surveillance of the CNS following Infection and Injury

“…Resident microglia upregulate PD-L1 after Theiler's murine encephalomyelitis virus (TMEV) infection, which was demonstrated in vitro to depend on IL-6 and IFN-I signaling [78]. Another study found that IFN-γ could also induce upregulation of PD-L1 on cultured microglia, and both IFN-γ-stimulated microglia and astrocytes were able to inhibit murine cytomegalovirus-specific CD8 + T cell activity when co-cultured together [79]. The importance of the PD-L1/PD-1 pathway was examined in vivo using the MHV infection model [80,81].…”