دورية أكاديمية
Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.
| العنوان: | Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. |
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| المؤلفون: | Vardhana SA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Hwee MA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Berisa M; The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Wells DK; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Yost KE; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., King B; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Smith M; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Herrera PS; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Medical College, New York, NY, USA., Chang HY; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA., Satpathy AT; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., van den Brink MRM; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Cross JR; The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Thompson CB; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. thompsonc@mskcc.org.; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. thompsonc@mskcc.org. |
| المصدر: | Nature immunology [Nat Immunol] 2020 Sep; Vol. 21 (9), pp. 1022-1033. Date of Electronic Publication: 2020 Jul 13. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature America Inc Country of Publication: United States NLM ID: 100941354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2916 (Electronic) Linking ISSN: 15292908 NLM ISO Abbreviation: Nat Immunol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Nature America Inc. c2000- |
| مواضيع طبية MeSH: | CD8-Positive T-Lymphocytes/*immunology , Lymphocytes, Tumor-Infiltrating/*immunology , Mitochondria/*metabolism , Neoplasms/*immunology, Adenosine Diphosphate/metabolism ; Animals ; Antigens, Neoplasm/immunology ; Antioxidants/pharmacology ; Cell Proliferation ; Cell Self Renewal ; Clonal Anergy/genetics ; Energy Metabolism ; Immune Tolerance ; Lymphocyte Activation ; Melanoma, Experimental ; Mice ; Mice, Inbred C57BL ; Oxidative Phosphorylation |
| مستخلص: | 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. |
| التعليقات: | Comment in: Cell Metab. 2020 Dec 1;32(6):905-907. (PMID: 33264601) |
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| معلومات مُعتمدة: | K08 CA237731 United States CA NCI NIH HHS; R01 HL147584 United States HL NHLBI NIH HHS; United States HHMI Howard Hughes Medical Institute; P30 CA008748 United States CA NCI NIH HHS; R25 AI140472 United States AI NIAID NIH HHS |
| المشرفين على المادة: | 0 (Antigens, Neoplasm) 0 (Antioxidants) 61D2G4IYVH (Adenosine Diphosphate) |
| تواريخ الأحداث: | Date Created: 20200715 Date Completed: 20201211 Latest Revision: 20220202 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC7442749 |
| DOI: | 10.1038/s41590-020-0725-2 |
| PMID: | 32661364 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1529-2916 |
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| DOI: | 10.1038/s41590-020-0725-2 |