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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