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

It is interesting that the frequency of effector CD8 + T cells remained high during late acute infection in PD-L1 −/− mice, but not in WT or PD-1 −/− mice. We therefore analyzed the role of another molecule as a possible receptor for PD-L1. Previously reverse signaling from CD80 after ligation to PD-L1 was described (36) . Thus, blocking anti-CD80 antibodies were used to prevent the interaction between PD-L1 and CD80 expressed on CD8 + T cells. However, the treatment of WT and PD-1 −/− mice with anti-CD80 antibodies did not lead to a detectible modulation of CD8 + T cell responses. The regulation of the functionality of CD8 + T cells is one important aspect of PD-1/PD-L1 signaling. In the LCMV model it was previously noted that deficiency for PD-1 led to a reduced production of IFN-γ in virus-specific CD8 + T cells after stimulation with viral antigens (10) . This observation was interpreted as an enhanced accumulation of "exhausted" terminally differentiated cells, which expressed the inhibitory receptors LAG3, CD160, 2B4, TIGIT, and Tim-3. In the FV model we previously showed that the population of PD-1 high CD8 + T cells, which also co-expressed other inhibitory receptors during the course of infection, produced significantly less cytokines in response to antigen re-stimulation than PD-1 low CD8 + T cells (10) . In contrast, they produced high amounts of granzymes and were responsible for the elimination of FV-infected target cells. Thus, the terminal differentiation was associated with an enhanced cytotoxic activity of CD8 + T cells. The co-expression of different inhibitory checkpoint receptors on terminally differentiated CD8 + T cells is an essential mechanisms for the control of potentially pathogenic CTLs. Interestingly, PD-1 also plays an important role in the regulation of longterm memory CD8 + T cells (10) . Currently it remains elusive why PD-L1 and PD-1 KO mice show such different CD8 + T cell responses and how these molecules influence the differentiation of the memory pool of CD8 + T cells during the later phase of viral infections.