Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity
The transcription factor Bach2 is a susceptible gene for numerous autoimmune diseases including systemic lupus erythematosus (SLE). Bach2−/− mice can develop a lupus-like autoimmune disease. However, the exact cellular and molecular mechanisms via which Bach2 protects the hosts from developing autoi...
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02050/full |
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| author | Heng Zhang Qianwen Hu Min Zhang Fang Yang Cheng Peng Zhen Zhang Chuanxin Huang |
| author_facet | Heng Zhang Qianwen Hu Min Zhang Fang Yang Cheng Peng Zhen Zhang Chuanxin Huang |
| author_sort | Heng Zhang |
| collection | DOAJ |
| description | The transcription factor Bach2 is a susceptible gene for numerous autoimmune diseases including systemic lupus erythematosus (SLE). Bach2−/− mice can develop a lupus-like autoimmune disease. However, the exact cellular and molecular mechanisms via which Bach2 protects the hosts from developing autoimmunity remains incompletely understood. Here, we report that Bach2 ablation on T cells, but not B cells, resulted in humoral autoimmunity, and this was associated with expansion of T follicular helper (Tfh) cells and abnormal germinal centers. Bach2 was down-regulated in Tfh cells and directly suppressed by the Tfh-defining transcription factor BCL6. Mechanistically, Bach2 directly suppresses the transcription of Cxcr5 and c-Maf, two key regulators of Tfh cell differentiation. Bach2-deficient Tfh cells were skewed toward the IL-4-producing subset, which induced IgG1 and IgE isotype switching of B cells. Heterozygous Bcl6 deficiency reduced the formation of germinal center and autoantibodies, and ameliorated the pathology in Bach2-deficient mice. Our findings identify Bach2 as a crucial negative regulator of Tfh cells at steady state and prove that Bach2 controls autoimmunity in part by restraining accumulation of pathogenic Tfh cells. |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T08:31:20Z |
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| spelling | doaj.art-ed1eeb8132344523b2b9f1209e566b9d2022-12-22T03:40:12ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-09-011010.3389/fimmu.2019.02050473348Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and AutoimmunityHeng Zhang0Qianwen Hu1Min Zhang2Fang Yang3Cheng Peng4Zhen Zhang5Chuanxin Huang6Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Faculty of Basic Medicine, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Faculty of Basic Medicine, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Children's Medical Center, Pediatric Translational Medicine Institute, Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Jiao Tong University, School of Medicine, Shanghai, ChinaKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Faculty of Basic Medicine, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Faculty of Basic Medicine, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Children's Medical Center, Pediatric Translational Medicine Institute, Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Jiao Tong University, School of Medicine, Shanghai, ChinaKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Faculty of Basic Medicine, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaThe transcription factor Bach2 is a susceptible gene for numerous autoimmune diseases including systemic lupus erythematosus (SLE). Bach2−/− mice can develop a lupus-like autoimmune disease. However, the exact cellular and molecular mechanisms via which Bach2 protects the hosts from developing autoimmunity remains incompletely understood. Here, we report that Bach2 ablation on T cells, but not B cells, resulted in humoral autoimmunity, and this was associated with expansion of T follicular helper (Tfh) cells and abnormal germinal centers. Bach2 was down-regulated in Tfh cells and directly suppressed by the Tfh-defining transcription factor BCL6. Mechanistically, Bach2 directly suppresses the transcription of Cxcr5 and c-Maf, two key regulators of Tfh cell differentiation. Bach2-deficient Tfh cells were skewed toward the IL-4-producing subset, which induced IgG1 and IgE isotype switching of B cells. Heterozygous Bcl6 deficiency reduced the formation of germinal center and autoantibodies, and ameliorated the pathology in Bach2-deficient mice. Our findings identify Bach2 as a crucial negative regulator of Tfh cells at steady state and prove that Bach2 controls autoimmunity in part by restraining accumulation of pathogenic Tfh cells.https://www.frontiersin.org/article/10.3389/fimmu.2019.02050/fullBach2T follicular helper cellsIL-4autoimmunityBCL6 |
| spellingShingle | Heng Zhang Qianwen Hu Min Zhang Fang Yang Cheng Peng Zhen Zhang Chuanxin Huang Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity Frontiers in Immunology Bach2 T follicular helper cells IL-4 autoimmunity BCL6 |
| title | Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity |
| title_full | Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity |
| title_fullStr | Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity |
| title_full_unstemmed | Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity |
| title_short | Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity |
| title_sort | bach2 deficiency leads to spontaneous expansion of il 4 producing t follicular helper cells and autoimmunity |
| topic | Bach2 T follicular helper cells IL-4 autoimmunity BCL6 |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02050/full |
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