Microbial-signaling pathways in dendritic cells in inflammatory bowel disease

Although pathological T cells that react to microbial commensals drive pathologies of inflammatory bowel disease (IBD), it is well known that interaction between T cell and microbe is indirect. T cell functions are dependent on an intermediary cell termed the antigen-presenting cell (APC). Dendritic cells (DCs) are key APCs well recognized to have nonredundant functions in microbial-sensing and T cell activation. In IBD pathogenesis, we have recently identified that DCs lacking the NF-kB suppressor, A20, activate pathological T cells and cause IBD. A20 suppresses multiple IBD-linked signaling pathways, including toll-like receptor and other pathways that use the signaling adaptor MyD88. Several studies support a pathogenic, and potentially exclusive role for MyD88 in IBD pathogenesis. By contrast, we report here that in the absence of MyD88, dendritic cells lacking A20 retain potent APC function to activate pathological, anti-commensal T cells that cause IBD. Surprisingly, loss of MyD88 resulted in a skewed IFNg:IL-17 ratio, in favor of anti-commensal T cell production of IL-17. In the lamina propria, IL-17⁺ T cells were preferentially expanded in the colon—this expansion occurred in a MyD88-independent fashion and resulted in almost overlapping abundance of cytokines in colonic tissue from mice whose DCs did or did not express MyD88. By contrast, MyD88 remarkably enhanced inflammatory cytokine expression in the small intestine, suggesting that signals that drive IBD pathogenesis could be distinct in different regions of intestine. These studies highlight a key role for MyD88-independent signals in the dynamic between host and commensal and pathogenesis of IBD.