Secreted IgM modulates the pool of IL-10 producing B Cells

Abstract Regulatory B cells (Bregs) are critical for maintaining immune tolerance, and alterations in Breg numbers has detrimental effects in inflammatory diseases, infection, and cancer. Bregs are found among most B cell subsets and act primarily by producing IL-10. Despite their importance, the signals that control Breg differentiation and maintenance are not well defined. Here, we demonstrate that mice incapable of secreting IgM (sIgM−/−) have drastically increased IL-10+ Bregs in lymphoid organs compared to wildtype (WT) mice. These IL-10+ Bregs are polyclonal and increased among all major B cell subsets. While newborn WT mice (<24 hr of age) harbor detectable serum IgM, IL-10+ B cell expansion occurs early after birth in both WT and sIgM−/− mice. However, IL-10+ Bregs contract only in WT but not in sIgM−/− mice, which is in parallel to rising levels of serum IgM in WT mice. 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, but rather the presence of sIgM. Mice that lack B cell-expressed high-affinity IgM receptor (FcμR) mirror the IL-10 phenotype in their B-1 and marginal zone B cells, 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 sIgM controls IL-10 competence in B cells via IgM binding receptors thereby revealing potential novel avenues for altering IL-10+ Breg induction in disease settings. Funding: T32AI134646, R01AR067751, R01AI127389, R01AI148652. Supported by grants from NIH (T32AI134646, R01AR067751, R01AI127389, R01AI148652)