Odorizzi, Pamela M.Pauken, Kristen E.Paley, Michael A.Sharpe, ArleneWherry, E. John2016-01-042015Odorizzi, Pamela M., Kristen E. Pauken, Michael A. Paley, Arlene Sharpe, and E. John Wherry. 2015. “Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells.” The Journal of Experimental Medicine 212 (7): 1125-1137. doi:10.1084/jem.20142237. http://dx.doi.org/10.1084/jem.20142237.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993586Programmed 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 (TEX 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+ TEX 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 TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.en-USJournal Article2016-01-0410.1084/jem.20142237