title: 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 on 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.
authors.affiliation: Department of Medicine, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, McGuire Translational Research Facility, Minneapolis, Minnesota.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Schachtele
authors.forename: Shuxian
authors.initials: S
authors.lastname: Hu
authors.forename: Wen S
authors.initials: WS
authors.lastname: Sheng
authors.forename: Manohar B
authors.initials: MB
authors.lastname: Mutnal
authors.forename: James R
authors.initials: JR
authors.lastname: Lokensgard
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D060890:B7-H1 Antigen / Q000378:metabolism*; D001921:Brain / Q000503:physiopathology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002908:Chronic Disease; D018920:Coculture Techniques; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004195:Disease Models, Animal; D004660:Encephalitis / Q000503:physiopathology*; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000502:physiology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007376:Interleukin-2; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma
keywords: astrocyte; encephalitis; immune suppression; major histocompatibility complex Class II; microglia; neuroinflammation