Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8⁺ T cells

Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8⁺ T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8⁺ T cells (T_EX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8⁺ T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8⁺ T_EX cells. These results demonstrate that CD8⁺ T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving T_EX cell populations from overstimulation, excessive proliferation, and terminal differentiation.