PD1 blockade improves survival and CD8+ cytotoxic capacity, without increasing inflammation, during normal microbial experience in old mice

Abstract

Listen

Translate article

Abstract The elderly and those with chronic diseases face a 2 to 10-fold higher risk of hospitalization and mortality post-infection compared with healthy adults. Disease severity in the elderly is often attributed to the aging of the immune system, including an expansion of exhausted T cells that contribute to inflammation and have impaired activation and function. It is unclear how exhausted T cells from aged individuals respond to infection and the impact of acute restoration of T cell activation produces functional cells that contribute to excessive inflammation. In a mouse model of normal microbial exposure (NME), old specific pathogen-free (SPF) mice exhibit 100% mortality when exposed to microbes ordinarily found in pet store mice. We show that old mice exposed to NME show increased expression of inflammatory pathways and elevated frequencies of a heterogenous exhausted CD8+ T cell pool that express different levels of PD1, TOX, and CXCR5. Treatment with an anti-PD1 monoclonal blocking antibody in old mice during NME significantly improves survival without altering the acute inflammatory response despite the potential for adverse events following checkpoint blockade. Anti-PD1-mediated survival depends on CD8+ but not CD4+ T cells. CD8+ PD1+ T cells from old mice given anti-PD1 have increased GzmB production. These data suggest a novel approach for reducing infection vulnerability in the aged by targeting CD8+ T cell exhaustion through checkpoint blockade immunotherapy.