Abstract
The programmed death (PD)-1/PD-L1 pathway is a well-recognized negative immune checkpoint that results in functional inhibition of T-cells. Microglia, the brain-resident immune cells are vital for pathogen detection and initiation of neuroimmune responses. Moreover, microglial cells and astrocytes govern the activity of brain-infiltrating antiviral T-cells through upregulation of PD-L1 expression. While T-cell suppressive responses within brain are undoubtedly beneficial to the host, preventing cytotoxic damage to this vital organ, establishment of a prolonged anti-inflammatory milieu may simultaneously lead to deficiencies in viral clearance. An immune checkpoint blockade targeting the PD-1: PD-L1 (B7-H1; CD274) axis has revolutionized contemporary treatment for a variety of cancers. However, the therapeutic potential of PD1: PD-L1 blockade therapies targeting viral brain reservoirs remains to be determined. For these reasons, it is key to understand both the detrimental and protective functions of this signaling pathway within the brain. This review highlights how glial cells use PD-L1 expression to modulate T-cell effector function and limit detrimental bystander damage, while still retaining an effective defense of the brain.
Highlights
While most researchers feel the term “immune privilege” is outdated and misleading when applied to the central nervous system (CNS), resident brain cells and their microenvironment do actively modulate immune responses [1]
Using our murine cytomegalovirus (MCMV) infection model, we have shown that both programmed death (PD)-1 and programmed death ligand-1 (PD-L1) knock-out animals display reduced number of CD8+ T-cells expressing brain-resident TRM (bTRM) phenotype within chronically-infected brains, when compared to wild type animals [41]
We have previously shown that programmed death receptor-1 (PD-1) KO animals displayed significantly greater mechanical hypersensitivity than wild type mice during chronic murine retroviral (LP-BM5) infection, which was associated with significantly increased infiltration of T-lymphocytes, macrophages, and microglial activation [46]
Summary
While most researchers feel the term “immune privilege” is outdated and misleading when applied to the central nervous system (CNS), resident brain cells and their microenvironment do actively modulate immune responses [1]. PD-1: PD-L1 interaction plays a critical role in eliciting the inhibitory second signals that are required for functional suppression of T-cell responses, commonly referred as T-cell “exhaustion” These exhausted phenotypes are characterized by decreased proliferative capacity, cytokine production, and cytotoxic effector functions (Figure 1) [6,7,8]. A basal level of PD-L1, is expressed on approximately 20% of microglia from uninfected mice, but induced expression is detectable on over 90% of the cells within one week following a viral brain infection [29] During neuroinflammation both microglial cells, as well as astrocytes, upregulate PD-L1 along with MHC I and MHC II, suggesting a role for resident glial cells in limiting CNS pathology [30]. We cannot exclude the possibility of microglia or T-cells interacting with themselves through the PD-1: PD-L1 pathway
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