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Selected mechanistically well-characterized microbiota-immune system interactions are depicted. Microbiome-derived TLR and NOD ligands and metabolites (e.g., SCFA, AhR ligands) act directly on enterocytes and intestinal immune cells, but can also reach remote tissues via the systemic circulation to modulate immunity. Foxp3+ Treg cells and Tfh/ex-Th17 cells localize in Peyer’s patches to promote class switch of B cells and production of secretory (s)IgA. These contribute to compartmentalization of commensal microbiota and regulate homeostatic microbiota composition. Intestinal colonization by SFB and many other commensals promotes differentiation of CD4+ Th17 cells. Moreover, SFB colonization elicits signaling via the ILC3/IL-22/SAA1/2 axis to induce IL-17A production by RORγt+ Th17 cells. ILC3-derived IL-22 contributes to containment of specific microbiota members by promoting IL-17A production by Th17 cells. Furthermore, deletion of ILC3-expressed MHCII activates commensal-specific CD4+ T cells to prevent an immune response against harmless colonizers. Early-life microbial colonization limits the expansion of iNKT cells, in part via production of sphingolipids, to prevent potential disease-promoting activity within the intestinal lamina propria and the lungs. Colonization with Bacteroides fragilis, a prominent member of mammalian intestinal microbiota, is able to promote CD4+ T cell differentiation and to balance Th1 and Th2 populations, an effect that relies on its PSA. PSA is taken up by lamina propria DCs through a TLR2-dependent mechanism and presented to naïve CD4+ T cells. In the simultaneous presence of activated TGF-β, these cells can differentiate to regulatory T cells (iTreg). IL-10 produced by these cells promotes immune homeostasis. Contrarily, IL-23 licensed through the same cascade promotes expansion of pro-inflammatory Th17 cells.