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T Cell Exhaustion

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Front. Immunol. | doi: 10.3389/fimmu.2019.00054

The PD-1/PD-L1 pathway effects the expansion and function of cytotoxic CD8+ T cells during an acute retroviral infection

 Paul David1,  Dominik Andre Megger2, Tamara Kaiser1, Tanja Werner1,  Jia Liu3,  Lieping Chen4, Barbara Sitek2, Ulf Dittmer1 and  Gennadiy Zelinskyy1*
  • 1Institute of Virology, University Hospital Essen, Germany
  • 2Medizinisches Proteom-Zentrum, Ruhr-Universität Bochum, Germany
  • 3Department of infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
  • 4Department of Immunobiology, School of Medicine, Yale University, United States

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: PD-1, Retrovirus, immunregulation, PD-L1 (B7-H1 CD274), Caspase 3, Apoptosis, CD8+ T cells

Received: 14 Sep 2018; Accepted: 10 Jan 2019.

Edited by:

Giuliana Mognol, La Jolla Institute for Allergy and Immunology (LJI), United States

Reviewed by:

Haidong Dong, Mayo Clinic College of Medicine & Science, United States
Dr. Kawaljit Kaur, University of California, Los Angeles, United States  

Copyright: © 2019 David, Megger, Kaiser, Werner, Liu, Chen, Sitek, Dittmer and Zelinskyy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Gennadiy Zelinskyy, Institute of Virology, University Hospital Essen, Essen, Germany,