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

Abstract

IL-10-producing regulatory B (B10) cells potently suppress allergic diseases, such as contact hypersensitivity (CHS). Splenic B10cells share overlapping phenotypic markers with CD5+ B1 Bcells, CD1dhiCD21+CD23- marginal zone (MZ) Bcells, and CD1dhiCD21+CD23+ T2-MZ precursor Bcells but do not exclusively belong to either subset. In this study we investigated the signaling mechanisms and a novel phenotypic parameter of B10cells. We performed microarray analysis comparing IL-10+ and IL-10- Bcells. B cell-specific phosphatase and tensin homolog (PTEN)-deficient mice, which exhibit aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in Bcells, were examined. Microarray analysis revealed that the PI3K-Akt pathway is important for IL-10 production in Bcells. PI3K-Akt pathway inhibitors reduced B10cell numbers invitro. B10 cell numbers were significantly increased in Bcell-specific PTEN-deficient mice. The CHS response was significantly diminished in PTEN-deficient mice. Unexpectedly, splenic B10cells 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 B10cells but also B1-B10cells were identified in the spleen. In addition, these 2 B10cell subsets were predominantly found within the CD9+CD80+ B-cell fraction. A novel splenic B1 regulatory cell subset (B1-B10cells) was identified. Our findings show that the PI3K-Akt pathway in Bcells is critical for B10cell development and CHS response and that CD9/CD80 coexpression is a novelphenotypic parameter for both MZ-B10 and B1-B10cells.