PD-1 regulates response to bystander activation of memory CD8 T cells

Abstract

Abstract Inflammatory cytokines, released in virally infected tissues, activate bystander memory T cells, expressing CD132 and CD122, in an antigen non-specific manner through signal 3 alone to provide early anti-viral protection in an NKG2D-dependent manner. We have previously observed that IL-2 stimulation expands bystander memory CD8 T cells that are NKG2D+/Programmed cell death protein 1(PD-1)-/CD25-. However, it is unclear if the presence of PD-1 regulates the ability of memory T cells to respond to signal 3 alone. In our study, IL-2 in vitro culture for 3 days results in proliferation of memory T cells in human PBMCs and preferential expansion of memory CD8 over CD4 T cells. PD-1- CD8 T cells had greater cycling of proliferation compared to PD-1+ CD8 T cells, as observed by dilution of CPeFluor670 staining. Similarly, mouse splenocytes proliferate in response to IL-2 in vitro. Ki67+ CD8 T cells were found to be predominantly PD-1−, while ConA-stimulated Ki67+ CD8 T cells were predominantly PD-1+. Adoptively transferred memory OTI CD8 T cells but not naïve OTI CD8 T cells expanded in vivo in the liver at 3–4 days post-infection with 2×10^3 PFU murine cytomegalovirus (MCMV), and a greater percentage of PD-1− OTI CD8 T cells were Ki67 positive compared to PD-1+ OTI CD8 T cells. We conclude that the expression of PD-1 on memory CD8 T cells can regulate response to signal 3 alone. Future studies will examine the impact of PD-1 blockade on the bystander response in anti-viral protection.