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ResearchIn-Press PreviewImmunologyMetabolism Open Access | 10.1172/JCI175897
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Zhou, J. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Gu, J. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Qian, Q. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Zhang, Y. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Huang, T. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Li, X. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Liu, Z. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Shao, Q. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Liang, Y. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Qiao, L. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Xu, X. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Chen, Q. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Xu, Z. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Li, Y. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Gao, J. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Pan, Y. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Wang, Y. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by O'Connor, R. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Hippen, K. in: JCI | PubMed | Google Scholar |
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Lu, L. in: JCI | PubMed | Google Scholar
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, China
4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America
5Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, United States of America
Find articles by Blazar, B. in: JCI | PubMed | Google Scholar |
Published September 12, 2024 - More info
Current research reports that lactate affects Treg metabolism, although the precise mechanism has only been partially elucidated. In this study, we presented evidence demonstrating that elevated lactate levels enhanced cell proliferation, suppressive capabilities, and oxidative phosphorylation (OXPHOS) in human Tregs. The expression levels of Monocarboxylate Transporters 1/2/4 (MCT1/2/4) regulate intracellular lactate concentration, thereby influencing the varying responses observed in naive Tregs and memory Tregs. Through mitochondrial isolation, sequencing, and analysis of human Tregs, we determined that Alpha-1,3-Mannosyl-Glycoprotein 2-Beta-N-Acetylglucosaminyltransferase (MGAT1) served as the pivotal driver initiating downstream N-glycosylation events involving progranulin (GRN) and hypoxia-upregulated 1 (HYOU1), consequently enhancing Treg OXPHOS. The mechanism by which MGAT1 was upregulated in mitochondria depended on elevated intracellular lactate that promoted the activation of XBP1s, which, in turn, supported MGAT1 transcription as well as the interaction of lactate with the translocase of the mitochondrial outer membrane 70 (TOM70) import receptor, facilitating MGAT1 translocation into mitochondria. Pre-treatment of Tregs with lactate reduced mortality in a xenogeneic graft-versus-host disease (GvHD) model. Together, these findings underscored the active regulatory role of lactate in human Treg metabolism through the upregulation of MGAT1 transcription and its facilitated translocation into the mitochondria.