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Abstract
Cytotoxic CD8+ T Lymphocytes (CTL) efficiently control acute virus infections but can become exhausted when a chronic infection develops. Signaling of the inhibitory receptor PD-1 is an important mechanism for the development of virus-specific CD8+ T cell dysfunction. However, it has recently been shown that during the initial phase of infection virus-specific CD8+ T cells express high levels of PD-1, but are fully competent in producing cytokines and killing virus-infected target cells. To better understand the role of the PD-1 signaling pathway in CD8+ T cell cytotoxicity during acute viral infections we analyzed the expression of the ligand on retrovirus-infected cells targeted by CTLs. We observed increased levels of PD-L1 expression after infection of cells with the murine Friend retrovirus (FV) or with HIV. In FV infected mice, virus-specific CTLs efficiently eliminated infected target cells that expressed low levels of PD-L1 or that were deficient for PD-L1 but the population of PD-L1high cells escaped elimination and formed a reservoir for chronic FV replication. Infected cells with high PD-L1 expression mediated a negative feedback on CD8+ T cells and inhibited their expansion and cytotoxic functions. These findings provide evidence for a novel immune escape mechanism during acute retroviral infection based on PD-L1 expression levels on virus infected target cells.
Highlights
IntroductionIn several chronic viral infections, such as Human Immunodeficiency virus (HIV) and Hepatitis C virus (HCV) infection of humans or Lymphocytic Choriomeningitis virus (LCMV) and Friend virus (FV) infection of mice, virus-specific CD8+ T cells become functionally exhausted with ongoing infection
Cytotoxic CD8+ T Lymphocytes (CTL) are crucial for controlling viruses and tumors
Virus-specific cytotoxic T cells can eliminate infected cells during acute viral infections, but in chronic infections these cells often become dysfunctional or “exhausted.” The inhibitory receptor programmed death 1 (PD-1) is involved in the suppression of cytotoxic T cell responses in chronic infections
Summary
In several chronic viral infections, such as Human Immunodeficiency virus (HIV) and Hepatitis C virus (HCV) infection of humans or Lymphocytic Choriomeningitis virus (LCMV) and Friend virus (FV) infection of mice, virus-specific CD8+ T cells become functionally exhausted with ongoing infection. PD-L1 is broadly expressed on different cells and organs while the other ligand for PD-1, PD-L2, is preferentially expressed on antigen presenting cells (APC) It has been shown in recent studies that effector T cells already up-regulate PD-1 during the acute phase of infection before virus becomes persistent or latent. The appearance of PD-1 on effector CD8+ T cells does not per se induce the exhaustion of these cells This suggests that the expression of the ligands for PD-1 might critically contribute to the functional involvement of PD-1 signaling in the development of viral chronicity. The in vivo regulation of PD-L1 expression during an ongoing infection and its effect on CTL killing of virus-infected target cells has not been studied until now
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