Secreted IgM modulates the pool of IL-10+ B cells

Abstract IL-10+ regulatory B cells (Bregs) are increasingly recognized as critical for maintaining immune tolerance, and alterations in Breg numbers can have detrimental effects in inflammatory diseases, infection, and cancer. Bregs are found among most B cell subsets and act primarily by producing the immunosuppressive cytokine IL-10. Despite their importance, the signals that control Breg differentiation are not well defined. Here, we demonstrate that mice incapable of secreting IgM (sIgM−/−) have significantly increased IL-10+ Bregs in lymphoid organs compared to wildtype mice. These IL-10 producing Bregs are polyclonal and increased among all major B cell subsets: B-1, follicular B, marginal zone B, T2-marginal zone precursors, and transitional B cells. SIgM−/− B cells that develop in the presence of circulating IgM express IL-10 similar to that of WT B cells within the same mouse indicating that the expansions in IL-10+ B cell populations are not due to B cell-intrinsic effects based on the inability to secrete IgM. Mice that lack B cell-expressed high-affinity IgM receptor (FcμR) mirrored the IL-10 phenotype in their B-1 and MZ, but not follicular B cells, suggesting that secreted IgM can act as a negative regulator of IL-10 expression in B cell subsets via binding to surface-expressed FcμR, and potentially other IgM binding receptors. Our data indicate that IgM binding receptors control IL-10 competence in some B cell subsets thereby revealing potential novel avenues for altering Breg induction in disease settings. Funding: T32AI134646, R01AR067751, R01AI127389.