Mucosal surfaces of mammals are exquisitely susceptible to colonization by pathogens and are populated by elaborate mucosal-associated lymphoid tissues that are rich in conventional and specialized cells of the innate and adaptive immune system.
All metazoan organisms have evolved a strategic alliance with commensal microorganisms. For example the gastrointestinal tract is heavily populated by commensal communities composed of species from the eukarya, archaea and bacteria. These communities are remarkably diverse and are essential for normal development and metabolism. In addition, recent studies identified alterations in the acquisition or composition of commensals that are associated with susceptibility to multiple metabolic and inflammatory diseases.
Simultaneous exposure to potential pathogens versus innocuous food antigens and beneficial commensal microorganisms creates a unique regulatory challenge for the gut-associated lymphoid tissues.
Intestinal epithelial cells (IECs) provide a crucial physical barrier to potentially invasive pathogens aided by the expression of intercellular tight junctions, an actin-rich brush border and a secreted glycocalyx. IECs also express germ-line encoded innate immune receptors and in vivo studies suggest that IECs routinely recognize and respond to commensal microorganisms in health and disease.
Mammalian IECs and commensal communities exhibit numerous adaptations that facilitate or limit inappropriate immune responses to commensals and thereby maintain symbiosis. These include restricted localization of pattern-recognition receptors on IECs and the capacity of commensals to limit innate immune signalling in host cells.
In addition to innate recognition of commensal microorganisms, IECs can directly regulate the functions of antigen-presenting cells, innate immune cells and lymphocytes in the intestinal microenvironment, suggesting that IECs are an essential lineage in the maintenance of intestinal immune homeostasis via translation of commensal-derived signals to the mucosal immune system.
Mucosal surfaces such as the intestinal tract are continuously exposed to both potential pathogens and beneficial commensal microorganisms. This creates a requirement for a homeostatic balance between tolerance and immunity that represents a unique regulatory challenge to the mucosal immune system. Recent findings suggest that intestinal epithelial cells, although once considered a simple physical barrier, are a crucial cell lineage for maintaining intestinal immune homeostasis. This Review discusses recent findings that identify a cardinal role for epithelial cells in sampling the intestinal microenvironment, discriminating pathogenic and commensal microorganisms and influencing the function of antigen-presenting cells and lymphocytes.
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Thanks to all current members of the Artis laboratory for useful discussions and contributions to this manuscript. Work in the laboratory is supported by the US National Institutes of Health (AI61570, AI74878, F31-GM82187, F32-AI72943, T32-AI007532-08, T32-CA09140-30), University of Pennsylvania Center for Infectious Diseases and University Research Fund, The Irvington Institute Fellowship Program of the Cancer Research Institute and The Crohn's and Colitis Foundation of America's William and Shelby Modell Family Foundation Research Award. Apologies to colleagues whose work and publications could not be referenced due to space constraints.
The author declares no competing financial interests.
- Gut-associated lymphoid tissues
(GALTs). Lymphoid structures and aggregates associated with the intestinal mucosa, specifically the tonsils, Peyer's patches, lymphoid follicles, appendix or coecal patch and mesenteric lymph nodes. They are enriched in conventional and unconventional lymphocytes and specialized dendritic-cell and macrophage subsets.
- Immunological hyporesponsiveness
A diminished degree of responsiveness to antigen or other stimulation. It is an active process, not simply a passive lack of response.
- Tight junctions
Specialized intercellular junctions that seal the apical epithelium. They are formed by several proteins including occludin and claudin, in which two plasma membranes form a sealing gasket around a cell (also known as zonula occludens). Tight junctions prevent fluid moving through the intercellular gaps and prevent lateral diffusion of membrane proteins between the apical and basolateral membranes.
- Brush border
The microvilli-covered surface found on the apical surface of epithelial cells that is coated in a rich glycocalyx of mucus and other glycoproteins. The microvilli contain many of the digestive enzymes and transporter systems that are involved in the metabolism and uptake of dietary materials, and provides a large surface area for absorption. Early anatomists noted that this structure appeared very much like the bristles of a paintbrush, hence the name brush borders.
- Goblet cell
A differentiated epithelial cell that secretes mucus.
- Lamina propria
Connective tissue that is found directly under the mucosal epithelial-cell surface of the gastrointestinal tract. It is traversed by blood and lymphoid vessels, physically supports epithelial cells through the basal membrane and is enriched in innate and adaptive immune cells.
- Peyer's patches
Groups of lymphoid nodules identified by Peyer in 1677 that are present in the small intestine (usually the ileum). They occur massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a subepithelial dome area, B-cell follicles and interfollicular T-cell areas.
- Pattern-recognition receptor
(PRR). A receptor that recognizes unique structures that are present at the surface of microorganisms. Signalling through PRRs leads to the production of pro-inflammatory cytokines and chemokines and to the expression of co-stimulatory molecules by antigen-presenting cells. The expression of co-stimulatory molecules, together with the presentation of antigenic peptides, by antigen-presenting cells couples innate immune recognition of pathogens with the activation of adaptive immune responses.
The development of new blood vessels from existing blood vessels.
- Adipose tissue
A type of connective tissue that is specialized for the storage of neutral lipids.
- Activation-induced cytidine deaminase
(AID). An RNA-editing enzyme that is necessary for somatic hypermutation and class-switch recombination.
Single-nucleotide differences in the sequence of genes that represent allelic variants. These differences might lead to altered structure and/or altered expression of gene products, ultimately leading to pathology.
The attachment of the small protein ubiquitin to lysine residues that are present in other proteins. This tags these proteins for rapid cellular degradation the proteasome.
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Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol 8, 411–420 (2008). https://doi.org/10.1038/nri2316
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