The PD-1/PD-L1 Pathway Affects the Expansion and Function of Cytotoxic CD8 + T Cells During an Acute Retroviral Infection

Front Immunol. 2019 Feb 5;10:54. doi: 10.3389/fimmu.2019.00054. eCollection 2019.

Abstract

Cytotoxic CD8+ T lymphocytes (CTL) efficiently control acute virus infections but can become exhausted when a chronic infection develops. The checkpoint receptor PD-1 suppresses the functionality of virus-specific CD8+ T cells during chronic infection. However, the role of the PD-L1/PD-1 pathway during the acute phase of infections has not been well characterized. In the current study the effects of PD-1 or PD-L1 deficiency on the CD8+ T cell response against Friend retroviral (FV) infection of knockout mice was analyzed during acute infection. We observed an enhanced proliferation, functional maturation, and reduced apoptosis of effector CD8+ T cells in the absence of PD-1 or PD-L1. The knockout of PD-L1 had a stronger effect on the functionality of CD8+ T cells than that of PD-1. Augmented CTL responses were associated with an improved control of FV replication. The strong phenotype of FV-infected PD-L1 knockout mice was independent of the interaction with CD80 as an additional receptor for PD-L1. Furthermore, we performed a detailed analysis of the production of different granzymes in virus-specific CD8+ T cells and observed that especially the simultaneous production of multiple granzymes in individual T cells (multifunctionality) was under the control of the PD-1/PD-L1 pathway. The findings from this study allow for a better understanding of the development of antiviral cytotoxic immunity during acute viral infections.

Keywords: CD8 T cells; PD-1; PD-L1; apoptosis; caspase 3; immunoregulation; retrovirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • B7-H1 Antigen / metabolism*
  • Caspases / metabolism
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Programmed Cell Death 1 Receptor / metabolism*
  • Proteome
  • Proteomics / methods
  • Retroviridae / immunology*
  • Retroviridae Infections / immunology*
  • Retroviridae Infections / metabolism*
  • Retroviridae Infections / virology
  • Signal Transduction*
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism*

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Programmed Cell Death 1 Receptor
  • Proteome
  • Caspases