Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells
Recent reports have shown the importance of IFN-γ and T-bet+ B cells in the pathology of SLE, suggesting the involvement of IFN-γ-producing T-bet+ CD4+ cells, i.e., Th1 cells. This study determined the changes in Th1 subsets with metabolic shift and their potential as therapeutic targets in SLE. Com...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2020.593103/full |
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| author | Shigeru Iwata Mingzeng Zhang Mingzeng Zhang He Hao He Hao Gulzhan Trimova Gulzhan Trimova Maiko Hajime Yusuke Miyazaki Naoaki Ohkubo Yurie Satoh Kanda Yasuyuki Todoroki Hiroko Miyata Masanobu Ueno Atsushi Nagayasu Shingo Nakayamada Kei Sakata Kei Sakata Yoshiya Tanaka |
| author_facet | Shigeru Iwata Mingzeng Zhang Mingzeng Zhang He Hao He Hao Gulzhan Trimova Gulzhan Trimova Maiko Hajime Yusuke Miyazaki Naoaki Ohkubo Yurie Satoh Kanda Yasuyuki Todoroki Hiroko Miyata Masanobu Ueno Atsushi Nagayasu Shingo Nakayamada Kei Sakata Kei Sakata Yoshiya Tanaka |
| author_sort | Shigeru Iwata |
| collection | DOAJ |
| description | Recent reports have shown the importance of IFN-γ and T-bet+ B cells in the pathology of SLE, suggesting the involvement of IFN-γ-producing T-bet+ CD4+ cells, i.e., Th1 cells. This study determined the changes in Th1 subsets with metabolic shift and their potential as therapeutic targets in SLE. Compared with healthy donors, patients with SLE had higher numbers of T-bethiCXCR3lo effector cells and T-bet+Foxp3lo non-suppressive cells, which excessively produce IFN-γ, and lower number of non-IFN-γ-producing T-bet+Foxp3hi activated-Treg cells. These changes were considered to be involved in treatment resistance. The differentiation mechanism of Th1 subsets was investigated in vitro using memory CD4+ cells obtained from healthy donors and patients with SLE. In memory CD4+ cells of healthy donors, both rapamycin and 2-deoxy-D-glucose (2DG) suppressed T-bet+Foxp3- cells, and induced T-bet+Foxp3+(lo/hi) cells. Rapamycin induced IFN-γ-producing T-bet+Foxp3lo cells accompanied with enhanced lipid metabolism, whereas 2DG induced IFN-γ-non-producing T-bet+Foxp3hi cells. In memory CD4+ cells of SLE patients, inhibition of fatty acid synthesis, but not β-oxidation, suppressed IFN-γ production, and up-regulated of Foxp3 expression in T-bet+Foxp3+ cells. Metabolic regulators such as fatty acid synthesis inhibitors may improve the pathological status by correcting Th1 subset imbalance and overproduction of IFN-γ in SLE. |
| first_indexed | 2024-12-17T22:34:06Z |
| format | Article |
| id | doaj.art-95ad77e1a47f4bab91a607e8855e9819 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T22:34:06Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-95ad77e1a47f4bab91a607e8855e98192022-12-21T21:30:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-11-011110.3389/fimmu.2020.593103593103Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 CellsShigeru Iwata0Mingzeng Zhang1Mingzeng Zhang2He Hao3He Hao4Gulzhan Trimova5Gulzhan Trimova6Maiko Hajime7Yusuke Miyazaki8Naoaki Ohkubo9Yurie Satoh Kanda10Yasuyuki Todoroki11Hiroko Miyata12Masanobu Ueno13Atsushi Nagayasu14Shingo Nakayamada15Kei Sakata16Kei Sakata17Yoshiya Tanaka18The First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanDepartment of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, ChinaThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanDepartment of Immuno-oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, ChinaThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanDepartment of Clinical Subjects, High School of Medicine, Faculty of Medicine and Health Care, Al-Farabi Kazakh National University, Almaty, KazakhstanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanResearch Unit/Immunology & Inflammation, Innovative Research Division, Mitsubishi Tanabe Pharma, Yokohama, JapanThe First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, JapanRecent reports have shown the importance of IFN-γ and T-bet+ B cells in the pathology of SLE, suggesting the involvement of IFN-γ-producing T-bet+ CD4+ cells, i.e., Th1 cells. This study determined the changes in Th1 subsets with metabolic shift and their potential as therapeutic targets in SLE. Compared with healthy donors, patients with SLE had higher numbers of T-bethiCXCR3lo effector cells and T-bet+Foxp3lo non-suppressive cells, which excessively produce IFN-γ, and lower number of non-IFN-γ-producing T-bet+Foxp3hi activated-Treg cells. These changes were considered to be involved in treatment resistance. The differentiation mechanism of Th1 subsets was investigated in vitro using memory CD4+ cells obtained from healthy donors and patients with SLE. In memory CD4+ cells of healthy donors, both rapamycin and 2-deoxy-D-glucose (2DG) suppressed T-bet+Foxp3- cells, and induced T-bet+Foxp3+(lo/hi) cells. Rapamycin induced IFN-γ-producing T-bet+Foxp3lo cells accompanied with enhanced lipid metabolism, whereas 2DG induced IFN-γ-non-producing T-bet+Foxp3hi cells. In memory CD4+ cells of SLE patients, inhibition of fatty acid synthesis, but not β-oxidation, suppressed IFN-γ production, and up-regulated of Foxp3 expression in T-bet+Foxp3+ cells. Metabolic regulators such as fatty acid synthesis inhibitors may improve the pathological status by correcting Th1 subset imbalance and overproduction of IFN-γ in SLE.https://www.frontiersin.org/articles/10.3389/fimmu.2020.593103/fullsystemic lupus erythematosusT-betIFN-γfatty acid synthesisimmunometabolism |
| spellingShingle | Shigeru Iwata Mingzeng Zhang Mingzeng Zhang He Hao He Hao Gulzhan Trimova Gulzhan Trimova Maiko Hajime Yusuke Miyazaki Naoaki Ohkubo Yurie Satoh Kanda Yasuyuki Todoroki Hiroko Miyata Masanobu Ueno Atsushi Nagayasu Shingo Nakayamada Kei Sakata Kei Sakata Yoshiya Tanaka Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells Frontiers in Immunology systemic lupus erythematosus T-bet IFN-γ fatty acid synthesis immunometabolism |
| title | Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells |
| title_full | Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells |
| title_fullStr | Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells |
| title_full_unstemmed | Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells |
| title_short | Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells |
| title_sort | enhanced fatty acid synthesis leads to subset imbalance and ifn γ overproduction in t helper 1 cells |
| topic | systemic lupus erythematosus T-bet IFN-γ fatty acid synthesis immunometabolism |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2020.593103/full |
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