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Intestinal epithelial cells: regulators of barrier function and immune homeostasis

Key Points

  • Intestinal epithelial cells (IECs) provide a physical and biochemical barrier that segregates host tissue and commensal bacteria to maintain intestinal homeostasis. Secretory IECs support this function through the secretion of mucins and antimicrobial peptides.

  • IECs maintain specialized pathways for the delivery of luminal antigens and bacteria to lamina propria-resident antigen-presenting cells.

  • Microbial signals are recognized by IECs to promote intestinal homeostasis. Host–commensal microorganism interactions not only support tissue repair in the setting of injury or acute inflammation but also promote the development of intestinal cancers during chronic inflammation.

  • IECs possess mechanisms for maintaining altered responsiveness to microbial signals that allow for tolerance to continuous exposure to commensal bacteria.

  • IECs convey microbial signals to mucosal immune cells and promote the coordination of appropriate immune responses against commensal bacteria and enteric pathogens. Interactions between antigen-presenting cells and IECs regulate B cell and T cell responses that act on the intestinal barrier.

  • Both innate and adaptive effector cell function and homeostasis are influenced by IEC-derived signals. This allows IECs to locally regulate immune response at the intestinal barrier and promote the maintenance of intestinal homeostasis.

Abstract

The abundance of innate and adaptive immune cells that reside together with trillions of beneficial commensal microorganisms in the mammalian gastrointestinal tract requires barrier and regulatory mechanisms that conserve host–microbial interactions and tissue homeostasis. This homeostasis depends on the diverse functions of intestinal epithelial cells (IECs), which include the physical segregation of commensal bacteria and the integration of microbial signals. Hence, IECs are crucial mediators of intestinal homeostasis that enable the establishment of an immunological environment permissive to colonization by commensal bacteria. In this Review, we provide a comprehensive overview of how IECs maintain host–commensal microbial relationships and immune cell homeostasis in the intestine.

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Figure 1: The IEC barrier.
Figure 2: Microbial recognition promotes IEC health and function.
Figure 3: IECs regulate innate and adaptive immunity.

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Acknowledgements

The authors thank all members of the Artis laboratory for discussions and critical reading of the manuscript. This work is supported by US National Institutes of Health grants (AI061570, AI095608, AI087990, AI074878, AI095466, AI106697, AI102942 and AI097333 to D.A.; T32AI00744 to L.W.P.), the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award (D.A.) and the Crohn's and Colitis Foundation of America (D.A.).

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The role of pattern recognition receptors (PRRs) in regulating intestinal epithelial cells (IECs) and tissue homeostasis. (PDF 713 kb)

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Glossary

Inflammatory bowel disease

(IBD). A chronic condition of the intestine characterized by severe inflammation and mucosal destruction. The most common forms of IBD in humans are ulcerative colitis and Crohn's disease, which have both distinct and overlapping pathological and clinical characteristics.

Mucins

Heavily glycosylated proteins that are the major component of the mucus that coats epithelial barrier surfaces.

Crypts

Tubular invaginations of the intestinal epithelium. Lining the base of the crypts are small intestinal Paneth cells, which produce numerous antimicrobial proteins, and stem cells, which continuously divide to give rise to the entire intestinal epithelium.

Villi

Projections of the intestinal epithelium into the lumen of the small intestine that have an outer layer consisting of mature, absorptive enterocytes, mucus-secreting goblet cells and enteroendocrine cells.

Pluripotent intestinal epithelial stem cells

(Pluripotent IESCs). Tissue-resident stem cells that undergo continuous self-renewal and are responsible for regenerating all lineages of mature intestinal epithelial cells, including enterocytes, enteroendocrine cells, goblet cells and Paneth cells.

Autophagy

A cellular process by which cytoplasmic organelles and macromolecular complexes are engulfed by double membrane-bound vesicles for delivery to lysosomes and subsequent degradation. This process is involved in constitutive turnover of proteins and organelles and is central to cellular activities that maintain a balance between the synthesis and breakdown of various proteins.

Unfolded protein response

(UPR). A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins, causes the arrest of the cell cycle and promotes apoptosis.

Plasma cells

Terminally differentiated cells of the B cell lineage that secrete large amounts of antibodies.

Lamina propria

Connective tissue that underlies the epithelium of the mucosa and contains stromal and haematopoietic cells.

Peyer's patches

Groups of lymphoid aggregates located in the submucosa of the small intestine that contain many immune cells, including B cells, T cells and dendritic cells. They have a luminal barrier consisting of specialized epithelial cells, called microfold cells, which sample the lumen and transport antigens.

Pattern-recognition receptors

(PRRs). Receptors that recognize structures shared by foreign microorganisms or endogenous molecules associated with pathogenesis. Signalling through these receptors promotes tissue-specific innate immune responses including the production of cytokines.

Toll-like receptor

(TLR). An evolutionarily conserved pattern-recognition receptor located at the cell surface or at intracellular membranes. The natural ligands of TLRs are conserved molecular structures found in bacteria, viruses and fungi.

NOD-like receptor

(NLR). A pattern-recognition receptor located in the cytosol. NLRs recognize a wide range of foreign structures and patterns associated with pathogenesis. Some members of this family form multiprotein complexes known as inflammasomes, which regulate the processing and secretion of pro-inflammatory cytokines.

RIG-I-like receptor

(RLR). A pattern-recognition receptor located in the cytosol that responds to viral RNA.

Dextran sodium sulphate

(DSS). A large polysaccharide that causes epithelial injury and inflammation in the intestinal tract and is commonly used in models of experimentally induced colitis for studying the response to intestinal injury.

Nuclear factor-κB

(NF-κB). A family of transcription factors important for pro-inflammatory and anti-apoptotic responses that are activated by the ubiquitin-dependent degradation of their respective inhibitors, members of the inhibitor of NF-κB (IκB) family. This process is mediated by the kinases, IκB kinase 1 (IKK1) and IKK2.

Inflammasomes

Multiprotein complexes that contain a member of the NOD-like receptor family, adaptor proteins and the protease caspase 1. These complexes regulate the catalytic processing and secretion of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and IL-18.

Reactive oxygen species

(ROS). Chemically reactive molecules containing oxygen that, when produced in large amounts, have pro-inflammatory and antimicrobial effects. Physiological levels of ROS have been shown to regulate cellular signalling pathways.

Viability-associated PAMPs

(Vita-PAMPs). Members of a special class of pathogen-associated molecular patterns recognized by the innate immune system to signify microbial life. These patterns differentiate dead and living microorganisms to allow for scaling of appropriate immune responses based on the level of threat the microbial signals represents.

Innate lymphoid cells

(ILCs). A group of innate immune cells that are lymphoid in morphology and developmental origin, but lack properties of adaptive B cells and T cells such as recombined antigen-specific receptors. They function in the regulation of immunity, tissue homeostasis and inflammation in response to cytokine stimulation.

Natural killer cells

(NK cells). A subset of innate lymphoid cells originally defined on the basis of their cytolytic activity against tumour targets but now recognized to serve a broader role in host defence and inflammation through the production of cytokines.

Class-switch recombination

(CSR). The process by which proliferating B cells rearrange their DNA to switch from expressing IgM (or another class of immunoglobulin) to expressing a different immunoglobulin heavy-chain constant region, thereby producing antibody with different effector functions.

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Peterson, L., Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14, 141–153 (2014). https://doi.org/10.1038/nri3608

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