An Essential Protective Role Of IL-10-Producing Regulatory B Cells Against IL-33-Mediated Mucosal Inflammation

Abstract

B cells with regulatory functions (Breg), as a unique cell lineage or lineages of the immune regulatory network, have attracted increasing attentions in recent years for their roles in maintaining peripheral tolerance. Interleukin 33 (IL-33), the newest IL-1 cytokine family member, has been shown to lead a double life with both pro- and anti-inflammatory properties. We report here that IL-33 treatment exacerbates, and induces an early onset of, the inflammatory bowel disease (IBD) in IL-10 deficient mice. Similarly treated wild-type control mice were however fully resistant to the IL-33-mediated disease induction. We demonstrated further that IL-33 treatment drove B cell proliferation and induced a phenotypically discrete subset (CD19+CD25+CD1dhiIgMhiCD23-) of IL-10 producing Breg-like precursor cells, which in return protected against the IL-33-mediated mucosal inflammation in normal mice. These IL-33-induced Bregs suppressed dose-dependently the proliferative responses of effector B cells in vitro and, upon adoptive transfer, significantly delayed the onset and reduced the severity of spontaneous IBD in the IL-10 deficient mice. Our findings thus provide clear evidence for an essential protective role hence therapeutic potential of the IL-10-producing Breg in the immune regulatory mechanisms against mucosal inflammatory disorders.