A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol 3-kinase-Akt pathway activation

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• 作者：Takashi Matsushita ; MD ; PhD^a ; ^{t-matsushita@med.kanazawa-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Doanh Le Huu ; MD ; PhD^a ; ^b ; Tadahiro Kobayashi ; MD ; PhD^a ; Yasuhito Hamaguchi ; MD ; PhD^a ; Minoru Hasegawa ; MD ; PhD^c ; Kazuhito Naka ; PhD^d ; Atsushi Hirao ; MD^e ; Masamichi Muramatsu ; MD ; PhD^f ; Kazuhiko Takehara ; MD ; PhD^a ; Manabu Fujimoto ; MD^g ; ^{fujimoto-m@umin.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Rodent ; B cells ; autoimmunity ; IL-10 ; marginal zone B cell ; B1 B cell ; phosphatidylinositol 3-kinase ; phosphatase and tensin homolog ; regulatory B cell
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：138
• 期：4
• 页码：1170-1182.e9
• 全文大小：5842 K

文摘

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, CD1d^hiCD21⁺CD23⁻ marginal zone (MZ) B cells, and CD1d^hiCD21⁺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.

3">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

30">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.