Phosphoinositide 3-Kinase P110δ-Signaling Is Critical for Microbiota-Activated IL-10 Production by B Cells that Regulate Intestinal Inflammation.

The phosphoinositide 3-kinase catalytic subunit p110 delta (PI3K delta) gene maps to a human inflammatory bowel diseases (IBD) susceptibility locus, and genetic deletion of PI3K delta signaling causes spontaneous colitis in mice. However, little is known regarding the role of PI3K delta on IL-10-producing B cells that help regulate mucosal inflammation in IBD. We investigated the role of PI3K delta signaling in B cell production of IL-10, following stimulation by resident bacteria and B cell regulatory function against colitis. In vitro, B cells from PI3K delta(D910A/D910A) mice or wild-type B cells treated with PI3K specific inhibitors secreted significantly less IL-10 with greater IL-12p40 following bacterial stimulation. These B cells failed to suppress inflammatory cytokines by co-cultured microbiota-activated macrophages or CD4(+) T cells. In vivo, co-transferred wild-type B cells ameliorated T cell-mediated colitis, while PI3K delta(D910A/D910A) B cells did not confer protection from mucosal inflammation. These results indicate that PI3K delta-signaling mediates regulatory B cell immune differentiation when stimulated with resident microbiota or their components, and is critical for induction and regulatory function of IL-10-producing B cells in intestinal homeostasis and inflammation.