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The PD-1/PD-L1 Axis and Virus Infections: A Delicate Balance


The PD-1/PD-L1 Axis and Virus Infections: A Delicate Balance

Günther Schönrich et al. Front Cell Infect Microbiol.


Programmed cell death protein (PD-1) and its ligands play a fundamental role in the evasion of tumor cells from antitumor immunity. Less well appreciated is the fact that the PD-1/PD-L1 axis also regulates antiviral immune responses and is therefore modulated by a number of viruses. Upregulation of PD-1 and its ligands PD-L1 and PD-L2 is observed during acute virus infection and after infection with persistent viruses including important human pathogens such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV). Experimental evidence suggests that insufficient signaling through the PD-1 pathway promotes immunopathology during acute infection by exaggerating primary T cell responses. If chronic infection is established, however, high levels of PD-1 expression can have unfavorable immunological consequences. Exhaustion and suppression of antiviral immune responses can result in viral immune evasion. The role of the PD-1/PD-L1 axis during viral infections is further complicated by evidence that PD-L1 also mediates inflammatory effects in the acute phase of an immune response. In this review, we discuss the intricate interplay between viruses and the PD-1/PD-L1 axis.

Keywords: PD-1; PD-L1; PD-L2; antiviral immune responses; viral immune evasion; virus-induced immunopathogenesis; viruses.


Figure 1
Figure 1
PD-L1 mediated viral regulation of T cell activation. Upper graph: In the absence of viral infection mature dendritic cells (DCs) express relatively low levels of PD-L1. Recognition of cognate antigen (Ag) bound to MHC class I molecules by T cell receptor (TCR) results in upregulation of PD-1 on T cells. DCs express co-stimulatory molecules CD80 and CD86 allowing efficient co-stimulation of T cells via CD28. The PD-1/PD-L1 axis is not co-inhibitory due to restriction by cis-PD-L1/CD80 interactions, and thus T cells are activated. Lower graph: In the context of viral infection DCs upregulate PD-L1 due to exposure to viral PAMPs and high levels of type I IFN. The restricting cis-PD-L1/CD80 interactions are most likely overwhelmed by virus-induced PD-L1 resulting in PD-1 signaling and prevention of T cell activation. The consequences of this for the generation of Tregs is as of yet unknown.
Figure 2
Figure 2
The PD-1/PD-L1 checkpoint in acute virus infection. Early phase: The infected tissue produces type I IFNs and possibly type III IFNs, which strongly induce antiviral IFN-stimulated genes (ISGs) but only moderate PD-L1 levels. Antiviral CD8+ T cells eliminate virus-infected cells. At this stage, the PD-1/PD-L1 checkpoint activity is low and does not restrict the antiviral immune response. Late Phase: Type II IFN and TNF-α is secreted by CD8+ T cells and other immune cells. In addition, hematopoietic cells such as plasmacytoid DCs (pDCs) produce large amounts of type I IFN. This results not only in virus elimination but also increases PD-L1 expression. The high checkpoint activity downregulates terminal differentiation of antiviral CD8+ T cells. Ideally, the strength and quality of the CD8+ T cell response is balanced out in such a way that the viral intruder is eliminated without causing immunopathology.

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