Lack of central memory cell generation by PD-1-deficient T cells under helper-deficient conditions

Abstract

Abstract An immune check point molecule PD-1 is associated with CD8 T cell exhaustion in tumor-infiltrating and chronic infection situations. Previously, we have demonstrated that CD8 T cells specific for a transplantation antigen, minor histocompatibility antigen H60, are exhausted when primed under CD4 helper-deficient conditions, showing PD-1hi phenotype, and the exhaustion is ascribed to inefficient antigen-clearance. We examined whether the helpless CD8 T cells could respond to re-challenge with H60 in absence of PD-1-mediated signaling using PD-1-deficient mice. Upon re-challenge with H60 of the PD-1-deficient mice, which had been primed against H60 under helper-deficient conditions, the H60-specific CD8 T cells expanded vigorously, exhibiting a memory-like response. Despite the restored proliferative potential to the antigen-re-encounter, the H60-specific PD-1-deficient CD8 T cells did not generate CD44hiCD6Lhicentral memory T cells under helper-deficient priming condition. They exhibited an exhausted status, with an increased CXCR3+KLRG1+ Tint cell fraction. When transferred to naïve hosts, PD-1-deficient helpless CD8 T cells showed reduced generation of central memory cells compared to their wild type counterparts. These results suggest that PD-1 signaling influences fate of effector CD8 T cells and provide information regarding CD8 T cell memory generation.