Programmed Death-1 Shapes Memory Phenotype CD8 T Cell Subsets in a Cell-Intrinsic Manner

Memory phenotype T cells, found in unimmunized mice, display phenotypic and functional traits of memory cells and provide essential protection against infections, playing a role in both innate and adaptive immune responses. Mechanisms governing homeostasis of these memory phenotype T cells remain ill-defined. In this study, we reveal a crucial role of the negative costimulator programmed death-1 (PD-1) in regulating developmental fates of memory phenotype cells. Thus, in lymphoid organs and tissues of PD-1 knockout (KO) mice a marked accumulation of functional effector memory (T(EM)) phenotype CD8 T cells was observed. T(EM) phenotype cells from PD-1 KO mice exhibit decreased proliferation but increased survival potential. These cells could produce effector molecules constitutively, in response to phorbol esters or through bystander activation by innate stimuli. Similarly, in lymphopenia-induced proliferating CD8 T cells, whereby normally naive T cells acquire a memory phenotype, skewing toward a T(EM) phenotype was prominent in the absence of PD-1. Acquisition of the T(EM) phenotype was a CD8 T cell-intrinsic phenomenon as demonstrated by mixed bone marrow transfer experiments. Importantly, adoptively transferred PD-1 KO CD8 central memory T (T(CM)) cells converted into the T(EM) phenotype, indicating that PD-1 sets a major checkpoint in the T(CM) to T(EM) phenotype differentiation process. This was reflected by distinct patterns of gene expression of PD-1 KO T(CM) phenotype cells revealed by global transcriptional analysis. Additionally, adoptively transferred PD-1 KO T(EM) phenotype cells converted to a lesser degree to a T(CM) phenotype. Collectively, these data suggest that PD-1 shapes memory phenotype CD8 T cell subsets.