Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor
Summary: Follicular regulatory T (TFR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain TFR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-11-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719313129 |
| _version_ | 1828756730288275456 |
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| author | Lei Wang Erxia Shen Lin Luo Hardis Rabe Qin Wang Jie Yin Xueying Yang Wenquan Liu Jessica M. Sido Hidetoshi Nakagawa Lin Ao Hye-Jung Kim Harvey Cantor Jianmei W. Leavenworth |
| author_facet | Lei Wang Erxia Shen Lin Luo Hardis Rabe Qin Wang Jie Yin Xueying Yang Wenquan Liu Jessica M. Sido Hidetoshi Nakagawa Lin Ao Hye-Jung Kim Harvey Cantor Jianmei W. Leavenworth |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | Summary: Follicular regulatory T (TFR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain TFR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3+ TFR cells is essential for TFR lineage stability, entry into the GC, and expression of regulatory activity. Deletion of Blimp1 in TFR cells reduced FoxP3 and CTLA-4 expression and increased pro-inflammatory cytokines and spontaneous production of autoantibodies, including elevated IgE. Maintenance of TFR stability reflected Blimp1-dependent repression of the IL-23R-STAT3 axis and activation of the CD25-STAT5 pathway, while silenced IL-23R-STAT3 or increased STAT5 activation rescued the Blimp1-deficient TFR phenotype. Blimp1-dependent control of CXCR5/CCR7 expression also regulated TFR homing into the GC. These findings uncover a Blimp1-dependent TFR checkpoint that enforces suppressive activity and acts as a gatekeeper of GC entry. : Wang et al. identify Blimp1 as a critical transcription factor for the proper positioning and stable expression of the suppressive activity of TFR cells that control GC responses. In the absence of Blimp1, unstable TFR cells prematurely migrate into the GC and differentiate into TFH-like cells to promote dysregulated GC responses. Keywords: humoral tolerance, regulatory T cells, follicular regulatory T cells, follicular helper T cells, germinal center response, germinal center positioning, Blimp1, TFR lineage stability |
| first_indexed | 2024-12-10T23:21:56Z |
| format | Article |
| id | doaj.art-4b1fa5a546ab4506a98a0a15fd1157b7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T23:21:56Z |
| publishDate | 2019-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-4b1fa5a546ab4506a98a0a15fd1157b72022-12-22T01:29:42ZengElsevierCell Reports2211-12472019-11-0129718481861.e6Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription FactorLei Wang0Erxia Shen1Lin Luo2Hardis Rabe3Qin Wang4Jie Yin5Xueying Yang6Wenquan Liu7Jessica M. Sido8Hidetoshi Nakagawa9Lin Ao10Hye-Jung Kim11Harvey Cantor12Jianmei W. Leavenworth13Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathogenic Biology and Immunology, Guangzhou Hoffmann Institute of Immunology, School of Basic Sciences, Guangzhou Medical University, Guangzhou 510182, ChinaDepartment of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226001, ChinaDepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, SwedenDepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology, Medical College of Soochow University, Suzhou, Jiangsu 215123, ChinaDepartment of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; Department of Cell Biology, Tianjin Medical University, Tianjin 300070, ChinaDepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Department of Parasitology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaDepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Corresponding authorDepartment of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; Corresponding authorSummary: Follicular regulatory T (TFR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain TFR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3+ TFR cells is essential for TFR lineage stability, entry into the GC, and expression of regulatory activity. Deletion of Blimp1 in TFR cells reduced FoxP3 and CTLA-4 expression and increased pro-inflammatory cytokines and spontaneous production of autoantibodies, including elevated IgE. Maintenance of TFR stability reflected Blimp1-dependent repression of the IL-23R-STAT3 axis and activation of the CD25-STAT5 pathway, while silenced IL-23R-STAT3 or increased STAT5 activation rescued the Blimp1-deficient TFR phenotype. Blimp1-dependent control of CXCR5/CCR7 expression also regulated TFR homing into the GC. These findings uncover a Blimp1-dependent TFR checkpoint that enforces suppressive activity and acts as a gatekeeper of GC entry. : Wang et al. identify Blimp1 as a critical transcription factor for the proper positioning and stable expression of the suppressive activity of TFR cells that control GC responses. In the absence of Blimp1, unstable TFR cells prematurely migrate into the GC and differentiate into TFH-like cells to promote dysregulated GC responses. Keywords: humoral tolerance, regulatory T cells, follicular regulatory T cells, follicular helper T cells, germinal center response, germinal center positioning, Blimp1, TFR lineage stabilityhttp://www.sciencedirect.com/science/article/pii/S2211124719313129 |
| spellingShingle | Lei Wang Erxia Shen Lin Luo Hardis Rabe Qin Wang Jie Yin Xueying Yang Wenquan Liu Jessica M. Sido Hidetoshi Nakagawa Lin Ao Hye-Jung Kim Harvey Cantor Jianmei W. Leavenworth Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor Cell Reports |
| title | Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor |
| title_full | Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor |
| title_fullStr | Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor |
| title_full_unstemmed | Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor |
| title_short | Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor |
| title_sort | control of germinal center localization and lineage stability of follicular regulatory t cells by the blimp1 transcription factor |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719313129 |
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