TY - JOUR
T1 - Glial cells suppress postencephalitic CD8+ T lymphocytes through PD-L1
AU - Schachtele, Scott J.
AU - Hu, Shuxian
AU - Sheng, Wen S.
AU - Mutnal, Manohar B.
AU - Lokensgard, James R.
PY - 2014/10
Y1 - 2014/10
N2 - 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.
AB - 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.
KW - Astrocyte
KW - Encephalitis
KW - Immune suppression
KW - Major histocompatibility complex class II
KW - Microglia
KW - Neuroinflammation
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U2 - 10.1002/glia.22701
DO - 10.1002/glia.22701
M3 - Article
C2 - 24890099
AN - SCOPUS:84906322876
SN - 0894-1491
VL - 62
SP - 1582
EP - 1594
JO - Glia
JF - Glia
IS - 10
ER -