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

Korbyn J Dahlquist, Matthew A Huggins, Matthew Yousefzadeh, Carolina Soto-Palma, Stephanie H Cholensky, Mark J Pierson, Declan M. Smith, Sara E Hamilton Hart, Christina D. Camell

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

By 2030, individuals 65 years of age or older will make up approximately 20% of the world’s population1. Older individuals are at the highest risk for mortality from infections, largely due to the pro-inflammatory, dysfunctional immune response, which is collectively known as immunosenescence2. During aging, CD8+ T cells acquire an exhausted phenotype, including increased expression of inhibitory receptors, such as programmed cell death 1 (PD1), a decline in effector function and elevated expression of inflammatory factors3–7. PD1 reduces T cell receptor activity via SHP2-dependent dephosphorylation of multiple pathways; accordingly, inhibiting PD1 activity through monoclonal antibodies increases CD8+ T cell effector response in young mice8–11. Attempts to improve CD8+ T cell responses by blocking inhibitory receptors are attractive; however, they can lead to adverse immune events due to overamplification of T cell receptor signaling and T cell activation12,13. Here we investigated the effect of monoclonal anti-PD1 immunotherapy during normal microbial experience, otherwise known as exposure to dirty mice, to determine whether it either improves exhausted CD8+ T cell responses in old mice or leads to a heightened inflammatory response and increased mortality.

Original languageEnglish (US)
JournalNature Aging
DOIs
StateAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

PubMed: MeSH publication types

  • Journal Article

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