Cold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseases
Abstract Background Regulatory B cell (Breg), known for its immunosuppressive properties through the provision of IL-10, plays a critical role in the control of inflammatory diseases. Although Breg has been discovered for over two decades in mammals, its existence in non-mammalian vertebrates remain...
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BMC
2025-06-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02311-y |
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| author | Jie Wang Wen-Jing Dong Tian-Tian Tian Chang-Song Wu Xiang-Yang Zhang Ya-Zhen Hu Yi-Ru Pan Xue-Qing Han Jun Li Carolina Tafalla Yong-An Zhang Xu-Jie Zhang |
| author_facet | Jie Wang Wen-Jing Dong Tian-Tian Tian Chang-Song Wu Xiang-Yang Zhang Ya-Zhen Hu Yi-Ru Pan Xue-Qing Han Jun Li Carolina Tafalla Yong-An Zhang Xu-Jie Zhang |
| author_sort | Jie Wang |
| collection | DOAJ |
| description | Abstract Background Regulatory B cell (Breg), known for its immunosuppressive properties through the provision of IL-10, plays a critical role in the control of inflammatory diseases. Although Breg has been discovered for over two decades in mammals, its existence in non-mammalian vertebrates remains unclear. Here, we aimed to explore the differentiation mechanism and functional profiles of teleost CD25L+ Breg to gain insights into the origin and evolution of Breg. Methods Flow cytometry, RNA-seq, qPCR, morphological analysis, immunoblotting, immunofluorescence, recombinant IL-35 stimulation, cell co-culture in Transwell system were performed to reveal the phenotypic features, differentiation mechanism and suppressive functions of teleost CD25L+ Breg. To elucidate the immunoregulatory role of CD25L+ Breg in vivo, bacterial infection and inflammatory bowel disease (IBD) models were established in teleost fish. Systemic and local inflammatory responses were assessed by flow cytometry, immunofluorescence, histological analysis, and cytokine measurements. Results Phenotypically, we identified a unique IgM+CD25L+ B cell subset, termed CD25L+ B cells, characterized by their capacity to produce IL-10 and IL-12p35 in a cold-blooded vertebrate, the grass carp. Mechanistically, IL-35 stimulation induced the differentiation of CD25L− B cells into CD25L+ B cells, promoting the production of IL-35 and IL-10 via STAT3 activation. Functionally, teleost CD25L+ B cells served as a conventional Breg subtype that exerted its immunosuppressive functions on effector T cells and neutrophils via cell contact or cytokine delivery. Upon bacterial infection, CD25L+ Breg increased earlier than CD25L+ Treg and produced IL-10. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced IBD model, Breg frequency and IL-10 levels increased significantly during IBD remission, and Breg adoptive transfer could prevent IBD development and contribute to intestinal tissue repair. Conclusions These novel findings reveal that fish have evolved Breg with specialized anti-inflammatory functions, providing evolutionary insights into the phylogenetic origin and functional conservation of Breg from fish to mammals. |
| format | Article |
| id | doaj-art-730c5d7b88a24973a36cfc1990abcf8c |
| institution | DOAJ |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-06-01 |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-730c5d7b88a24973a36cfc1990abcf8c2025-08-20T03:22:54ZengBMCCell Communication and Signaling1478-811X2025-06-0123112210.1186/s12964-025-02311-yCold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseasesJie Wang0Wen-Jing Dong1Tian-Tian Tian2Chang-Song Wu3Xiang-Yang Zhang4Ya-Zhen Hu5Yi-Ru Pan6Xue-Qing Han7Jun Li8Carolina Tafalla9Yong-An Zhang10Xu-Jie Zhang11National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversityState Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, Fujian Agriculture and Forestry UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversitySchool of Science and Medicine, Lake Superior State UniversityAnimal Health Research Center (CISA), National Institute for Agricultural and Food Research and Technology (INIA), National Research Council (CSIC)National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, College of Fisheries, Huazhong Agricultural UniversityAbstract Background Regulatory B cell (Breg), known for its immunosuppressive properties through the provision of IL-10, plays a critical role in the control of inflammatory diseases. Although Breg has been discovered for over two decades in mammals, its existence in non-mammalian vertebrates remains unclear. Here, we aimed to explore the differentiation mechanism and functional profiles of teleost CD25L+ Breg to gain insights into the origin and evolution of Breg. Methods Flow cytometry, RNA-seq, qPCR, morphological analysis, immunoblotting, immunofluorescence, recombinant IL-35 stimulation, cell co-culture in Transwell system were performed to reveal the phenotypic features, differentiation mechanism and suppressive functions of teleost CD25L+ Breg. To elucidate the immunoregulatory role of CD25L+ Breg in vivo, bacterial infection and inflammatory bowel disease (IBD) models were established in teleost fish. Systemic and local inflammatory responses were assessed by flow cytometry, immunofluorescence, histological analysis, and cytokine measurements. Results Phenotypically, we identified a unique IgM+CD25L+ B cell subset, termed CD25L+ B cells, characterized by their capacity to produce IL-10 and IL-12p35 in a cold-blooded vertebrate, the grass carp. Mechanistically, IL-35 stimulation induced the differentiation of CD25L− B cells into CD25L+ B cells, promoting the production of IL-35 and IL-10 via STAT3 activation. Functionally, teleost CD25L+ B cells served as a conventional Breg subtype that exerted its immunosuppressive functions on effector T cells and neutrophils via cell contact or cytokine delivery. Upon bacterial infection, CD25L+ Breg increased earlier than CD25L+ Treg and produced IL-10. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced IBD model, Breg frequency and IL-10 levels increased significantly during IBD remission, and Breg adoptive transfer could prevent IBD development and contribute to intestinal tissue repair. Conclusions These novel findings reveal that fish have evolved Breg with specialized anti-inflammatory functions, providing evolutionary insights into the phylogenetic origin and functional conservation of Breg from fish to mammals.https://doi.org/10.1186/s12964-025-02311-yRegulatory B cellIL-10IL-35Inflammatory bowel diseaseEvolution |
| spellingShingle | Jie Wang Wen-Jing Dong Tian-Tian Tian Chang-Song Wu Xiang-Yang Zhang Ya-Zhen Hu Yi-Ru Pan Xue-Qing Han Jun Li Carolina Tafalla Yong-An Zhang Xu-Jie Zhang Cold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseases Cell Communication and Signaling Regulatory B cell IL-10 IL-35 Inflammatory bowel disease Evolution |
| title | Cold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseases |
| title_full | Cold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseases |
| title_fullStr | Cold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseases |
| title_full_unstemmed | Cold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseases |
| title_short | Cold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseases |
| title_sort | cold blooded vertebrates evolved regulatory b cells to participate in inflammatory diseases |
| topic | Regulatory B cell IL-10 IL-35 Inflammatory bowel disease Evolution |
| url | https://doi.org/10.1186/s12964-025-02311-y |
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