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

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B214
Abstract ID: 5536

Presenting Author:
Korbyn JV Dahlquist , Graduate Student at Univ. of Minnesota, Twin Cities

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.