Epithelial crosstalk at the microbiota-mucosal interface

Abstract

This article provides an overview of how intestinal epithelial cells (IEC) recognize commensals and how they maintain host-bacterial symbiosis. Endocrine, goblet cells, and enterocytes of the intestinal epithelium express a range of pattern recognition receptors (PRR) to sense the presence of microbes. The best characterized are the Toll-like receptors (TLR) and nucleotide oligomerization domain-like receptors (NLR), which play a key role in pathogen recognition and the induction of innate effectors and inflammation. Several adaptations of PRR signaling have evolved in the gut to avoid uncontrolled and potentially destructive inflammatory responses toward the resident microbiota. PRR signaling in IEC serve to maintain the barrier functions of the epithelium, including the production of secretory IgA (sIgA). Additionally, IECs play a cardinal role in setting the immunosuppressive tone of the mucosa to inhibit overreaction against innocuous luminal antigens. This includes regulation of dendritic cells (DC), macrophage and lymphocyte functions by epithelial secreted cytokines. These immune mechanisms depend heavily on IEC recognition of microbes and are consistent with several studies in knockout mice that demonstrate TLR signaling in the epithelium has a profoundly beneficial role in maintaining homeostasis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Simplified cartoon of PRR signaling in epithelial cells showing only the canonical pathway of NF-κB activation and some of the key receptors, adaptors, and kinases involved. After stimulation of TLRs or NLRs by microbial products, the inhibitor of IkB is phosphorylated, leading to its degradation and the translocation of NF-κB into the nucleus where it activates the expression of cytokines and chemokines and other effectors.

Fig. 2.

The role of IEC signaling in B cell class switching. Microbial recognition by IEC leads to the production of the cytokine TGF-β and the TNF-family member APRIL that promote IgA class switching in B cells. DC and macrophages acquire antigens from commensal bacteria promiscuously sampled by M cells within Peyer's patches. TSLP produced by TLR signaling in the epithelium enhances production of APRIL and BAFF by DC. Additionally retinoic acid produced by mucosal DC appears to determine the specificity of IgA class switch recombination in the mucosa. Activated T cells may also provide cognate help for T cell-dependent switching to IgA, although a significant proportion of IgA class-switching is T cell-independent.

Fig. 3.

Mucosal CD103+ DC are conditioned in the peripheral tissues by epithelial production of TSLP and TGF-β, which endows DC with the ability to prime noninflammatory responses and induce regulatory T cells. When they receive an inflammatory or danger signal, they begin to mature, and the expression of CCR7 increases allowing the DC to enter lymph vessels and migrate to the draining lymph nodes. In the T cell areas retinoic acid, the acid form of vitamin A plays an important role in the ability of DC to up-regulate homing receptors on lymphocytes. Retinoic acid (RA) is also an important cofactor for the differentiation of Foxp3+ Tregs and has been shown to inhibit the generation of Th17 cells.