PD-1 Blockade Reverses Obesity-Mediated T Cell Priming Impairment

Catherine T. Le, Lam T. Khuat, Sofia E. Caryotakis, Marilyn Wang, Cordelia Dunai, Alan V. Nguyen, Logan V. Vick, Kevin M. Stoffel, Bruce R. Blazar, Arta M Monjazeb, William J. Murphy, Athena Soulika

Research output: Contribution to journalArticlepeer-review

Abstract

Despite obesity reaching pandemic proportions, its impact on antigen-specific T cell responses is still unclear. We have recently demonstrated that obesity results in increased expression of PD-1 on T cells, and checkpoint blockade targeting PD-1/PD-L1 surprisingly resulted in greater clinical efficacy in cancer therapy. Adverse events associated with this therapy center around autoimmune reactions. In this study, we examined the impact of obesity on T cell priming and on autoimmune pathogenesis using the mouse model experimental autoimmune encephalomyelitis (EAE), which is mediated by autoreactive myelin-specific T cells generated after immunization. We observed that diet-induced obese (DIO) mice had a markedly delayed EAE onset and developed milder clinical symptoms compared to mice on control diet (CD). This delay was associated with impaired generation of myelin-specific T cell numbers and concurrently correlated with increased PD-L1 upregulation on antigen-presenting cells in secondary lymphoid organs. PD-1 blockade during the priming stage of EAE restored disease onset and severity and increased numbers of pathogenic CD4+ T cells in the central nervous system (CNS) of DIO mice to similar levels to those of CD mice. Administration of anti–PD-1 after onset of clinical symptoms did not increase EAE pathogenesis demonstrating that initial priming is the critical juncture affected by obesity. These findings demonstrate that obesity impairs antigen-specific T cell priming, but this can be reversed with PD-1 blockade. Our results further suggest that PD-1 blockade may increase the risk of autoimmune toxicities, particularly in obesity.

Original languageEnglish (US)
Article number590568
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - Oct 29 2020

Keywords

  • dendritic cells
  • experimental autoimmune encephalomyelitis
  • priming
  • programmed cell death protein 1
  • T cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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