In contrast to antibody-induced inflammatory responses, some B-cell subpopulations suppress inflammation through the production of interleukin (IL)-10. However, the mechanisms underlying Il10 gene expression during B-cell development is elusive. Here, we identify IgM B220 CD138 cells responsible for marked IL-10 production in the bone marrow and spleen of mice. These murine IL-10-producing cells predominantly secrete IgM and have unique characteristics of long-lived plasma cells in spite of high expression of surface IgM. We found that IL-10 production is strongly correlated with the expression level of Prdm1 (encoding the Blimp-1 protein), an essential regulator of plasma cell development. Furthermore, overexpression of Prdm1 induces Il10 expression in naïve B cells. Immunoglobulin class-switching recombination events resulted in the downregulation of both Il10 and Prdm1 expression in differentiating B cells. Thus, the prolonged elevation of Blimp-1 expression during the formation of IgM CD138 cells without class-switching elicits IL-10 production. Adoptive transfer of Il10-deficient B cells into B-cell-deficient mice demonstrated that IgM CD138 cell-derived IL-10 supports the survival of class-switched plasma cells and their antibody production in response to antigen challenge. These findings reveal an important role for IL-10 secretion by IgM CD138 cells in the complete and efficient humoral response.
Lnk/Sh2b3 is an adaptor protein that negatively regulates cytokine signaling in lymphohematopoiesis. A missense variant within the LNK/SH2B3 gene has been reported to be a risk variant for several autoimmune diseases, including diabetes. We found that glucose tolerance and insulin responses were impaired in Lnk mice. Moreover, immune cells such as group 1 innate lymphoid cells (G1-ILCs), CD8 T cells, and M1 macrophages accumulated in adipose tissue. When Lnk mice were crossed with Il15 mice or depleted of G1-ILCs but not CD8 T cells, glucose intolerance and adipose inflammation were ameliorated. Lnk G1-ILCs showed activated phenotypes as well as enhanced reactivity for IL-15, and administration of a JAK inhibitor improved glucose tolerance. Accordingly, a high-fat diet greatly worsened glucose intolerance in Lnk mice. Thus, Lnk/Sh2b3 controls homeostasis in adipose tissue and reduces the risk of onset of diabetes by regulating the expansion and activation of IL-15-dependent adipose G1-ILCs.
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