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

David, Paul; Megger, Dominik A.; Kaiser, Tamara; Werner, Tanja; Liu, Jia; Chen, Lieping; Sitek, Barbara; Dittmer, Ulf; Zelinskyy, Gennadiy

Cytotoxic CD8 + T Lymphocytes (CTL) are crucial for controlling viruses and tumors. However, 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. There is compelling evidence that this T cell exhaustion contributes significantly to the establishment of viral chronicity. The functional impairment of CTLs is associated with the expression of inhibitory checkpoint receptors and is a result of signaling from these receptors after binding to their ligands (1) . The therapeutic prevention of the interaction between inhibitory ligands and checkpoint receptors with blocking antibodies reconstituted the functionality of exhausted cells during chronic infection and in some malignancies (1, 2) . The so far most important and best characterized inhibitory receptor is the Programmed Cell Death Receptor-1 (PD-1) and its ligand PD-L1. Interestingly, activated virus-specific CD8 + T cells enhance the expression of PD-1 already very early after antigen stimulation (3) . During many acute viral infections activated PD-1 positive effector cells are not exhausted (4) . The expansion of PD-1 expressing CD8 + T cells with full effector functions has been reported during the acute infections of humans with Epstein Barr virus (EBV) (5), Hepatitis C virus (HCV) (6) , or Hepatitis B virus (HBV) (7) as well as in monkeys infected with Simian Immunodeficiency virus (SIV) (8) , or SIV-HIV hybrid virus (SHIV) (9) . In experiments, LCMV-specific CD8 + T cells with PD-1 knockout were transferred into LCMV-infected mice and subsequently developed exhaustion, enhanced proliferation during early infection, and enhanced apoptosis (10) . Furthermore, the SIV study provides evidence that T cell receptor stimulation itself induces PD-1 expression on CD8 + T cells (8) .