Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen Journal Article


Authors: Vardhana, S. A.; Hwee, M. A.; Berisa, M.; Wells, D. K.; Yost, K. E.; King, B.; Smith, M.; Herrera, P. S.; Chang, H. Y.; Satpathy, A. T.; van den Brink, M. R. M.; Cross, J. R.; Thompson, C. B.
Article Title: Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen
Abstract: The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Journal Title: Nature Immunology
Volume: 21
Issue: 9
ISSN: 1529-2908
Publisher: Nature Publishing Group  
Date Published: 2020-09-01
Start Page: 1022
End Page: 1033
Language: English
DOI: 10.1038/s41590-020-0725-2
PUBMED: 32661364
PROVIDER: scopus
PMCID: PMC7442749
DOI/URL:
Notes: MSK author Pamela Hatfield's last name is listed as "Herrera" in this Publication -- Source: Scopus
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MSK Authors
  1. Justin Robert Cross
    111 Cross
  2. Craig Bernie Thompson
    153 Thompson
  3. Melody Smith
    33 Smith
  4. Santosha Adipudi Vardhana
    102 Vardhana
  5. Bryan Christopher King
    11 King
  6. Mirela Berisa
    6 Berisa
  7. Madeline Anne Hwee
    4 Hwee