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

In the current study, the murine Friend retrovirus model was used to characterize the effects of PD-1 inhibitory checkpoint receptor expressed on CTLs or its ligand PD-L1 for the regulation of these cells during an acute infection. FV is an oncogenic retroviral complex that can induce erythroleukemia in susceptible mice. However, resistant mouse strains, like the C57BL/6 mice that were used in this study, mount a potent anti-viral immune response during the acute phase of infection that prevents the onset of leukemia (11) . Despite this efficient initial viral immunity, FV eventually escapes from T cell mediated immune control and establishes a chronic infection (12) . We previously showed that activated CD8 + T cells upregulate the expression of PD-1 but remain fully functional during the first 2 weeks of FV infection (4) . These cells were highly cytotoxic but sensitive to PD-1 mediated suppression. The signal that progressively induced T cell exhaustion in the CD8 + T cell population came from PD-L1 expressing virusinfected cells. FV infection up-regulated PD-L1 in a subset of CTL target cells, which subsequently escaped elimination by PD-1 high CTLs and consequently suppressed their functionality (13) . In previous studies it was also shown that regulatory CD4 + T cells (Tregs) (14) and myeloid derived suppressor cells (MDSCs) (15) were involved in the functional down-regulation of CTLs during the late phase of acute infection. Despite growing numbers of studies analyzing the role of PD-1 during chronic infections, the functional effects of this receptor and its ligand during the early phase of antiviral immune responses remain incompletely understood. In the current study PD-1 −/− and PD-L1 −/− mice with gene defects in the respective genes were used for the analysis of the effects of the PD-1/PD-L1 pathway on the virus-specific CTL response during an acute viral infection. We observed that mainly PD-1 regulated the magnitude of the virus-specific CD8 + T cell response, and in this way, determined the efficacy of antiviral immunity. The current study provides new data about the functional role of inhibitory checkpoint receptors during an acute viral infection.