Cytokines 2017

Regulatory B (Breg) cell that produce IL-10 negatively regulates autoimmune diseases and allergic diseases, such as contact hypersensitivity (CHS). Breg cell shares overlapping phenotype markers with CD1d^hiCD5⁺ B cell subset and CD1d^hiCD21^hiCD23^hi T2-marginal zone (MZ) precursor B cell subset, but does not exclusively belong to either subset. Furthermore, the signaling mechanisms of Breg cell remain unclear. In this study, we investigated a novel phenotypic marker and signaling mechanisms of Breg cell using microarray analysis. Microarray analysis revealed PI3K-Akt pathway is important for IL-10 production in B cells. PI3K-Akt pathway inhibitors reduced IL-10 production in B cells. Furthermore, Breg cells were significantly increased in B cell-specific PTEN-deficient mice, which exhibit aberrant activation of the PI3K-Akt pathway in B cells. The CHS response was significantly diminished in B cell-specific PTEN-deficient mice. Unexpectedly, splenic Breg cells in B cell-specific PTEN-deficient mice were found within B1-B cell subset but not within MZ-B cell subset, which is similar to CD1d^hiCD5⁺ B cell or T2-MZ precursor B cell subsets. By contrast, splenic Breg cells in wild type mice were found within not only MZ-B cell subset but also B1-B cell subset, and both subsets inhibited CHS response. In addition, the Akt phosphorylation in both MZ-B cell and B1-B cell subsets was enhanced. Microarray analysis also revealed CD9⁺CD80⁺ is a novel phenotypic marker for Breg cell. In addition, both MZ-Breg cell and B1-Breg cell subsets belong to CD9⁺CD80⁺ Breg cells. The current study shows the PI3K-Akt pathway is important for Breg cell and CHS response. Furthermore, CD9⁺CD80⁺ is a novel phenotypic marker for both MZ-Breg and B1-Breg cell subsets.