Takashi Matsushita1, Doanh Le Huu2, Tadahiro Kobayashi3, Yasuhito Hamaguchi3, Minoru Hasegawa4, Kazuhito Naka5, Atsushi Hirao6, Masamichi Muramatsu7, Kazuhiko Takehara3, Manabu Fujimoto8. 1. Department of Dermatology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. Electronic address: t-matsushita@med.kanazawa-u.ac.jp. 2. Department of Dermatology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; Department of Dermatology and Venereology, Hanoi Medical University, Hanoi, Vietnam. 3. Department of Dermatology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. 4. Department of Dermatology, University of Fukui, Fukui, Japan. 5. Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 6. Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 7. Department of Molecular Genetics, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. 8. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Japan. Electronic address: fujimoto-m@umin.ac.jp.
Abstract
BACKGROUND: IL-10-producing regulatory B (B10) cells potently suppress allergic diseases, such as contact hypersensitivity (CHS). Splenic B10 cells share overlapping phenotypic markers with CD5+ B1 B cells, CD1dhiCD21+CD23- marginal zone (MZ) B cells, and CD1dhiCD21+CD23+ T2-MZ precursor B cells but do not exclusively belong to either subset. OBJECTIVE: In this study we investigated the signaling mechanisms and a novel phenotypic parameter of B10 cells. METHOD: We performed microarray analysis comparing IL-10+ and IL-10- B cells. B cell-specific phosphatase and tensin homolog (PTEN)-deficient mice, which exhibit aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in B cells, were examined. RESULTS: Microarray analysis revealed that the PI3K-Akt pathway is important for IL-10 production in B cells. PI3K-Akt pathway inhibitors reduced B10 cell numbers in vitro. B10 cell numbers were significantly increased in B cell-specific PTEN-deficient mice. The CHS response was significantly diminished in PTEN-deficient mice. Unexpectedly, splenic B10 cells in these mice were found within the B1 B-cell subset but not within the MZ B-cell subset. In wild-type mice not only MZ B10 cells but also B1-B10 cells were identified in the spleen. In addition, these 2 B10 cell subsets were predominantly found within the CD9+CD80+ B-cell fraction. CONCLUSION: A novel splenic B1 regulatory cell subset (B1-B10 cells) was identified. Our findings show that the PI3K-Akt pathway in B cells is critical for B10 cell development and CHS response and that CD9/CD80 coexpression is a novel phenotypic parameter for both MZ-B10 and B1-B10 cells.
BACKGROUND:IL-10-producing regulatory B (B10) cells potently suppress allergic diseases, such as contact hypersensitivity (CHS). Splenic B10 cells share overlapping phenotypic markers with CD5+ B1 B cells, CD1dhiCD21+CD23- marginal zone (MZ) B cells, and CD1dhiCD21+CD23+ T2-MZ precursor B cells but do not exclusively belong to either subset. OBJECTIVE: In this study we investigated the signaling mechanisms and a novel phenotypic parameter of B10 cells. METHOD: We performed microarray analysis comparing IL-10+ and IL-10- B cells. B cell-specific phosphatase and tensin homolog (PTEN)-deficient mice, which exhibit aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in B cells, were examined. RESULTS: Microarray analysis revealed that the PI3K-Akt pathway is important for IL-10 production in B cells. PI3K-Akt pathway inhibitors reduced B10 cell numbers in vitro. B10 cell numbers were significantly increased in B cell-specific PTEN-deficientmice. The CHS response was significantly diminished in PTEN-deficientmice. Unexpectedly, splenic B10 cells in these mice were found within the B1 B-cell subset but not within the MZ B-cell subset. In wild-type mice not only MZ B10 cells but also B1-B10 cells were identified in the spleen. In addition, these 2 B10 cell subsets were predominantly found within the CD9+CD80+ B-cell fraction. CONCLUSION: A novel splenic B1 regulatory cell subset (B1-B10 cells) was identified. Our findings show that the PI3K-Akt pathway in B cells is critical for B10 cell development and CHS response and that CD9/CD80 coexpression is a novel phenotypic parameter for both MZ-B10 and B1-B10 cells.
Keywords:
B cells; B1 B cell; IL-10; Rodent; autoimmunity; marginal zone B cell; phosphatase and tensin homolog; phosphatidylinositol 3-kinase; regulatory B cell
Authors: Sophina H Taitano; Luciën E P M van der Vlugt; Molly M Shea; Jennifer Yang; Nicholas W Lukacs; Steven K Lundy Journal: J Immunol Date: 2018-08-20 Impact factor: 5.422
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