PD-1 Impairs CD8(+) T Cell Granzyme B Production in Aged Mice during Acute Viral Respiratory Infection

CD8(+) T cell dysfunction contributes to severe respiratory viral infection outcomes in older adults. CD8(+) T cells are the primary cell type responsible for viral clearance. With increasing age, CD8(+) T cell function declines in conjunction with an accumulation of cytotoxic tissue-resident memory (T(RM)) CD8(+) T cells. We sought to elucidate the role of PD-1 signaling on aged CD8(+) T cell function and accumulation of CD8(+) T(RM) cells during acute viral respiratory tract infection, given the importance of PD-1 regulating CD8(+) T cells during acute and chronic infections. PD-1 blockade or genetic ablation in aged mice yielded improved CD8(+) T cell granzyme B production comparable to that in young mice during human metapneumovirus and influenza viral infections. Syngeneic transplant and adoptive transfer strategies revealed that improved granzyme B production in aged Pdcd1(−/−) CD8(+) T cells was primarily cell intrinsic because aged wild-type CD8(+) T cells did not have increased granzyme B production when transplanted into a young host. PD-1 signaling promoted accumulation of cytotoxic CD8(+) T(RM) cells in aged mice. PD-1 blockade of aged mice during rechallenge infection resulted in improved clinical outcomes that paralleled reduced accumulation of CD8(+) T(RM) cells. These findings suggest that PD-1 signaling impaired CD8(+) T cell granzyme B production and contributed to CD8(+) T(RM) cell accumulation in the aged lung. These findings have implications for future research investigating PD-1 checkpoint inhibitors as a potential therapeutic option for elderly patients with severe respiratory viral infections.