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 M. Soulika

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12 Scopus citations


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
StatePublished - Oct 29 2020

Bibliographical note

Funding Information:
This work was funded by National Institutes of Health (grant numbers NIH RO1 CA214048, NIH RO1 CA095572, and NIH RO1 HL56067), by the National Center for Advancing Translational Sciences, National Institutes of Health (grant number UL1 TR001860 and linked award TL1 TR001861), and Shriners Hospitals for Children—Northern California (grant number: 85114-NCA-18). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Flow cytometry core was supported by the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (grant number P30 CA093373).

Funding Information:
We would like to thank W. Ma from the Murphy Lab, T. Burns and D. Pleasure from the Pleasure Lab, and E. Dunn and S. Carroll in the UC Davis Veterinary Medicine Comparative Pathology Laboratory for their technical expertise and help. We would also like to thank the other members in the Murphy lab for providing feedback and suggestions during preparation of the manuscript.

Publisher Copyright:
© Copyright © 2020 Le, Khuat, Caryotakis, Wang, Dunai, Nguyen, Vick, Stoffel, Blazar, Monjazeb, Murphy and Soulika.


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


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