PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape from CD8+ T Cell Killing

PLoS Pathog. 2015 Oct 20;11(10):e1005224. doi: 10.1371/journal.ppat.1005224. eCollection 2015 Oct.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cytotoxicity, Immunologic / immunology*
  • Flow Cytometry
  • Humans
  • Immune Evasion / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / immunology
  • Real-Time Polymerase Chain Reaction
  • Retroviridae / immunology
  • Retroviridae Infections / immunology*

Substances

  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft with grants to GZ (ZE 893/1-1 and Transregio 60, Project B8N), and with a grant to UD (Transregio 60, Project B4), and to KKD (DI 1914/1-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.