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Background: Regulatory B cells that exhibit the cell-surface CD1dhiCD5+ phenotype and produce IL-10 are termed B10 cells. Although B10 cells exert potent suppressive functions in patients with various allergic and autoimmunity disorders, the precise signaling mechanisms required for B10 cell functions remain unknown. B-cell linker protein (BLNK) is an essential component of the B-cell antigen receptor signaling pathway and is required for optimal B-cell development. Objective: We sought to elucidate the signaling pathways that are responsible for IL-10 production in B10 cells and in vivo mechanisms of how impaired B10 cell functions influence allergic and autoimmune responses. Method: For in vitro assays, splenic CD1dhiCD5+ B cells from BLNK-deficient (BLNK −/−) mice were analyzed for intracellular signaling pathways and cytokine production. Contact hypersensitivity (CHS) and experimental autoimmune encephalomyelitis were examined by using BLNK −/− mice. Results: Although the CD1dhiCD5+ B-cell population was present in BLNK −/− mice, IL-10 production was impaired both in vitro and in vivo. BLNK −/− mice had exaggerated CHS and experimental autoimmune encephalomyelitis responses, which were normalized by adoptive transfer of splenic CD1dhiCD5+ B cells from wild-type mice. In mice with CHS, BLNK −/− mice exhibited decreased B-cell and regulatory T-cell percentages and increased CD8+ T-cell percentages in the skin and lymph nodes. In vitro BLNK was required for LPS-induced signal transducer and activator of transcription 3 phosphorylation in CD1dhiCD5+ B cells. Finally, secreted IL-10 leads to autocrine expansion of IL-10–producing B cells. Conclusion: BLNK serves as a critical signaling component for B10 cell function by mediating IL-10 production. [Copyright &y& Elsevier]