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

of PD-1 signaling on CD8 + T cell activation, expansion and contraction during the acute phase of a virus infection. In the PD-1 and PD-L1 KO mice all cells are deficient for these molecules, so we cannot distinguish between direct or indirect effects on CD8 + T cells. For example, the absence of PD-L1 has a significant effect on the differentiation of myeloid cells (33) . The following experiment was designed to test the direct influence of PD-L1 on the expansion of effector CD8 + T cells. CD8 + T cells were isolated from the spleens of CD45.1 × TCR-Tg mice (T cell receptor transgenic mice, with CD8 + T cells that recognize the immunodominant gagL epitope of FV) and were transferred into WT or PD-L1 −/− mice 1 day prior to FV infection ( Figure 4A) . The expansion of transferred cells was characterized on day 8 and day 12 after infection by staining for CD45.1 + CD8 + T cells. Most of the expanded CD8 + CD45.1 + T cells from 8 days FV-infected WT and PD-L1-/-mice upregulated PD-1 on the cell surface ( Figure 4B) . Thus, this checkpoint receptor may be involved in the regulation of expanded virus-specific cells from donor mice. At day 8 after infection, the numbers of CD8 + T cells were significantly higher in the spleen and BM of infected PD-L1 −/− mice as compared to WT mice (Figures 4C,D) . Also numbers of CD8 + CD45.1 + T cells producing GzmB in the spleen and BM of PD-L1 −/− mice were significantly higher than in WT mice at day 8 after FV infection (Figures 4E,F) . In contrast, at day 12 after infection the numbers of transferred virus-specific CD8 + T cells and the numbers of cells producing of GzmB were similar in both groups of mice. Thus, the transfer experiment confirmed the data from PD-L1 −/− mice that the expansion and functional maturation of CD8 + T cells during the early phase of an acute infection is regulated by the PD-L1/PD-1 pathway.