Glial cells suppress postencephalitic CD8+ T lymphocytes through PD‐L1. Issue 10 (3rd June 2014)

• Record Type: Journal Article
• Authors: Schachtele, Scott J.; Hu, Shuxian; Sheng, Wen S.; Mutnal, Manohar B.; Lokensgard, James R.
• Is Part Of: Glia. Volume 62:Issue 10(2014:Oct.)
• Page Start: 1582
• Page End: 1594
• Publication Date: 2014-06-03
• Subjects: Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.22701
• Languages: English
• ISSNs: 0894-1491

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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<sup>+</sup> 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<sup>+</sup> T‐cells persisting within the brain expressed PD‐1. Conversely, activated microglia expressed PD‐L1. <italic>In vitro</italic>, 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<sup>+</sup> 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<sup>+</sup> T‐cell co‐cultures. Using <italic>ex vivo</italic> cultures of brain leukocytes, including microglia and CD8<sup>+</sup> 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<sup>+</sup> T‐cells stimulated with MCMV IE1<sub>168–176</sub> 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. GLIA 2014;62:1582–1594</p> </abstract>