PD-1 plays a stimulatory role in CD8 T cell priming and an inhibitory role after activation (88.43)

Abstract

Abstract The expression of the program death-1 (PD-1) receptor, a member of the CD28 costimulatory receptor family, is induced by T cell activation. It is still controversial whether PD-1 plays an inhibitory role or act as a stimulatory factor in T cell activation. It is yet to be determined if PD-1 contributes to age-related defect in CTL response to virus. We hypothesized that in the initiation stage, PD-1 plays a stimulatory role in T cell activation, and that upregulated PD-1 on activated T cells delivers an inhibitory signal to T cells. In the present study, we measured PD-1 expression in aged mice after adenovirus (Ad) infection and correlated it with Ad specific CTL activation using an MHC I tetramer, Db-E1Bp. First, to determine the need for PD-1 in the primary CTL response, we administered Ad into PD-1 deficient mice (PD-1 KO) in parallel with CD28 deficient (CD28 KO) mice. There is a significant decrease in the generation of Db-E1Bp+CD8+ cells in both CD28 KO and PD-1 KO mice 8 days after Ad infection, compared to WT mice (1% and 4% of total CD8+ cells, respectively, compared to 9%. p < 0.05). We next demonstrated that PD-1 upregulation was associated with a decrease in Ad specific CTL response and a defect in activation induced cell death in aged mice. Eight days after Ad infection, 83% of Db-E1Bp+CD8+ cells expressed high level of PD-1 in 24-mo old mice, compared to 16% in young mice (p < 0.05). The expression of PD-1 on non-activated, Db-E1Bp−CD8+ cells was similar in young and old mice. These results indicated that PD-1 on naïve CD8 T cells plays a costimulatory role in T cell activation and high level of PD-1 expression induced upon activation turn it into an inhibitory receptor. Its inhibitory function might also account for the defective activation induced cell death in virus specific CD8 T cells in old mice.