Modulation of immune development and function by intestinal microbiota

Abstract

The immune system must constantly monitor the gastrointestinal tract for the presence of pathogens while tolerating trillions of commensal microbiota. It is clear that intestinal microbiota actively modulate the immune system to maintain a mutually beneficial relation, but the mechanisms that maintain homeostasis are not fully understood. Recent advances have begun to shed light on the cellular and molecular factors involved, revealing that a range of microbiota derivatives can influence host immune functions by targeting various cell types, including intestinal epithelial cells, mononuclear phagocytes, innate lymphoid cells, and B and T lymphocytes. Here, we review these findings, highlighting open questions and important challenges to overcome in translating this knowledge into new therapies for intestinal and systemic immune disorders.

Keywords: commensals; immune regulation; microbiota; mucosal immunity.

Fig. 1. Examples of microbiota influence on the innate immune responses.

The microbiota regulates intestinal immune responses primarily through the production of PAMPs and metabolic by-products. Recognition of commensal-derived PAMPs e.g. LPS by the intestinal epithelial cells (IEC) induces secretion of antimicrobial peptide - RegIIIγ that mediates colonization resistance in the gut. RegIIIγ is also induced indirectly through flagellin recognition by CD103⁺ lamina propria dendritic cells (DC) that in turn activate innate lymphoid cells (ILC) to secrete IL-22, a strong AMP inducer. Microbiota derived signals induce IL-18 production from the IEC through activation of NLRs. The microbiota digests complex plant polysaccharides producing short chain fatty acids (SCFA) as by-products. These SCFA induce secretion of IL-18 form IEC via signaling through GPR109a receptor. Certain SCFAs such as acetate produced by Bifidobacterium promotes epithelial cell barrier function by inducing an anti-apoptotic response in the IEC. Microbiota derived sphingolipids presented on CD1d by DC inhibit colonic iNKT cells.

Fig. 2. Examples of microbiota influence on the adaptive immune responses.

Signals from commensal bacteria induce production of BAFF, APRIL and TGF-β in the intestinal epithelial cells (IEC) and dendritic cells (DC), which in turn promotes the differentiation of B cells into IgA⁺ plasma cells. After activation by commensal bacteria follicular dendritic cells (FDC) also promote the differentiation of B cells into IgA⁺ plasma cells, as they are a main producers of TGF-β in the Payer’s patches. Commensals can regulate function of the innate lymphoid cells (ILC) which in turn promote T cell independent IgA induction through the interaction of membrane bound lymphotoxin (LTα₁β₂) with DC, whereas soluble form of ILC-derived lymphotoxin (sLTα₃) supports T cell dependent IgA induction by promoting T cell homing to the lamina propria, presumably influencing Tfh population. Segmented filamentous bacteria (SFB) are found in close contact with IEC where they may induce SAA that stimulates DC and promotes the differentiation of Th17 cells. Presentation of SFB antigens by DC on MHC II is also needed for Th17 induction. Microbiota derived signals induce IL-1β production by mononuclear phagocytes that promotes Th17 differentiation. ATP produced by certain commensals activates DCs and leads to induction of Th17 cells. Th17 cells can differentiate into Tfh cell and therefore contribute to IgA production. Polysaccharide A (PSA) produced by Bacteroides fragilis directly promotes Treg cell differentiation via TLR2 or indirectly by conditioning DCs. Microbiota derived short chain fatty acids (SCFA), a by-product of metabolism, may promote Treg cell generation either directly through signalling via GPCR43 or indirectly via IEC. Clostridium species belonging to clusters IV, XIVa and XVIII induce TGF-β production in IEC, which promotes Treg differentiation in the colon.