Intestinal epithelial cells as mediators of the commensal-host immune crosstalk

Abstract

Commensal bacteria regulate the homeostasis of host effector immune cell subsets. The mechanisms involved in this commensal-host crosstalk are not well understood. Intestinal epithelial cells (IECs) not only create a physical barrier between the commensals and immune cells in host tissues, but also facilitate interactions between them. Perturbations of epithelial homeostasis or function lead to the development of intestinal disorders such as inflammatory bowel diseases (IBD) and intestinal cancer. IECs receive signals from commensals and produce effector immune molecules. IECs also affect the function of immune cells in the lamina propria. Here we discuss some of these properties of IECs that define them as innate immune cells. We focus on how IECs may integrate and transmit signals from individual commensal bacteria to mucosal innate and adaptive immune cells for the establishment of the unique mucosal immunological equilibrium.

Figure 1

Commensal bacteria regulate IEC barrier functions. Microbiota induce epithelial barrier mechanisms: (1) Commensal bacteria, such as Bifidobacteria, produce SCFAs, which protect IECs from epithelial apoptosis induced by enteropathogenic Escherichia coli and inhibit NF-κB activation. (2) Dimeric IgA produced by mucosal plasma cells binds to polymeric immunoglobulin receptor (poly-Ig receptor) expressed on basolateral side of IECs and is transcytosed to the apical surface, where it is released as SIgA. Both IgA class switching and poly-Ig receptor expression are regulated by commensal bacteria. (3) Commensal bacteria induce multiple AMPs such as RegIIIβ, RegIIIγ, Angiogenin-4 from Paneth cells in a TLR-dependent manner. (4) Commensal bacteria strengthen tight junctions (TJ). Epithelial tight junction protein, ZO-1, is upregulated by commensals in a TLR-dependent manner. (5) Commensal bacteria induce the expression of Fut2 and fucosylation of surface proteins on IECs. (6) Commensal bacterial products such as lipopolysaccharide (LPS) and peptidoglycan (PGN) induce mucus production from goblet cells.

Figure 2

IECs integrate signals from the commensal microbiota to regulate homeostasis of mucosal immune cells in the LP. (a) Commensal bacteria regulate the recruitment, maintenance and function of intraepithelial lymphocytes (IELs) (left panel), T-cell-independent IgA induction (middle panel), and innate lymphoid cell homeostasis (right panel). (Left panel) Recruitment of IELs is mediated by epithelial E-cadherin and αEβ7 on IELs. IL-7 and IL-15 secretion by IECs induced by commensal bacteria leads to expansion of IELs. IEL function is regulated by ligation of IEL TCRs by thymus leukemia antigen on IECs. (Middle panel) Commensal-derived lipopolysaccharide (LPS) recruits B-cells and plasma cells by inducing CCL20 and CCL28, respectively, from IECs. Commensal bacteria and commensal-derived LPS also induce BAFF and APRIL production from IECs. TSLP produced by IECs acts on LP DCs and induces APRIL secretion. Combined, these cytokines elicit IgA class switching in a T-cell-independent manner. (Right panel) Commensal bacteria induce CCL20 and IL-25 from IECs, which respectively regulate recruitment and IL-22 production of ILCs. Extension of dendrites between IECs by CX3CR1⁺ Mfs/DC are regulated by commensal bacteria and epithelial CX3CL1. Semaphorin 7A (Sema7A) on IECs induces IL-10 from CX3CR1⁺ Mf. Dashed arrows indicate IEC molecules induced by commensal bacteria. (b) Commensal bacteria induce production of various cytokines from IECs, which may help modulate mucosal T-cell differentiation. IEC-derived RA and TGF-β instruct DCs to induce Treg. DCs directly stimulated by commensal bacteria produce IL-12 and induce Th1 cells. IECs stimulated by commensal bacteria produce TSLP to upregulate IL-10 production by DCs, leading to Th2 cell induction. SFB are able to attach to IECs and induce serum amyloid A (SAA). DCs stimulated by SAA produce IL-6 and IL-23, and may drive Th17 cell differentiation. Clostridia clusters IV and XIVa induce TGF-β from IECs, which may promote differentiation of Treg.