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  • Review Article
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The light and dark sides of intestinal intraepithelial lymphocytes

Nature Reviews Immunology volume 11, pages 445–456 (2011)Cite this article

Subjects

Key Points

  • Intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system.

  • IELs are almost exclusively antigen-experienced T cells that are heterogeneous in phenotype, ontogeny, antigen specificity and function.

  • IELs consist of two main subtypes. The natural IELs consist of T cell receptor-αβ (TCRαβ)+ T cells and TCRγδ+ T cells that express CD8αα or are negative for both CD4 and CD8. These IELs acquire their activated and functional phenotype, in part, during self-agonist antigen-based selection in the thymus. Induced IELs consist of CD4+ and CD8αβ+ TCRαβ+ T cells that often co-express CD8αα. They are the progeny of naive T cells that are conventionally selected in the thymus and acquire their activated phenotype and functional differentiation post-thymically in response to cognate antigens encountered in the periphery.

  • IELs serve unique and dual functions. Their 'light side' is their ability to preserve the integrity of the epithelium and prevent damage induced by invading pathogens (protective immunity) or induced by excessive or aberrant inflammatory immune responses.

  • IELs also have a 'dark side': as they are located within the fragile, single cell layer of the epithelium and possess potent cytotoxic effector machinery, they can target the epithelium in a destructive way. Consequently, IELs may drive immunopathological responses in chronic inflammatory diseases, such as inflammatory bowel disease and coeliac disease.

Abstract

The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system. As IELs are located at this critical interface between the core of the body and the outside environment, they must balance protective immunity with an ability to safeguard the integrity of the epithelial barrier: failure to do so would compromise homeostasis of the organism. In this Review, we address how the unique development and functions of intestinal IELs allow them to achieve this balance.

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Figure 1: Thymic and peripheral differentiation of natural and induced IELs.
Figure 2: Kinetics of the accumulation of natural and induced IELs.
Figure 3: The 'light' and 'dark' sides of intestinal IELs.

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Acknowledgements

This is the manuscript number 1364 of the La Jolla Institute for Allergy and Immunology, California, USA. We thank F. van Wijk for helpful discussions and M. Cheroutre for her contribution. Work in the H.C. laboratory is supported by the National Institutes of Health (RO1 AI050265-06) and the La Jolla Institute for Allergy and Immunology. Work in the D.M. laboratory is supported by The Rockefeller University, New York, USA, and by the Crohn's & Colitis Foundation of America.

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  1. Laboratory of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, 92037, California, USA

    Hilde Cheroutre & Florence Lambolez

  2. Laboratory of Mucosal Immunology, The Rockefeller University, New York, 10065, New York, USA

    Daniel Mucida

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  1. Hilde Cheroutre
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Glossary

Pathogens

Opportunistic organisms that cause acute or chronic disease following host infection. Derived from the Greek word 'pathos', which means 'suffering'.

Intraepithelial lymphocytes

(IELs). These lymphocyte populations consist mostly of T cells and are found within the epithelial layer of mammalian mucosal linings, such as the gastrointestinal tract and reproductive tract. However, unlike conventional naive T cells, IELs are antigen- experienced T cells and, on encountering antigens, they immediately release cytokines or mediate killing of infected target cells.

Thymus leukaemia antigen

(TLA). A non-polymorphic, non-classical MHC class I molecule (MHC class I-b family) with a restricted expression pattern. It is constitutively expressed on intestinal epithelial cells and can be induced on antigen-presenting cells. TLA is structurally incapable of binding or presenting peptide antigens and it does not engage with T cell receptors. However, the α3 extracellular domain of TLA interacts with CD8α. TLA displays stronger affinity for CD8αα homodimers compared with CD8αβ heterodimers, and CD8αα expression can be detected with TLA-specific tetramers.

Lamina propria

Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

Microbiota

The microorganisms present in normal, healthy individuals. These microorganisms live mostly in the digestive tract but are also found in some other tissues.

Germ-free mice

Mice born and raised in sterile isolators. They are devoid of colonizing microorganisms, but after they have been experimentally colonized by known bacteria, they are said to be gnotobiotic.

Gut-associated lymphoid tissues

Lymphoid structures and aggregates associated with the intestinal mucosa, specifically the tonsils, Peyer's patches, lymphoid follicles, appendix and caecal patch. Enriched in lymphocytes and specialized dendritic cell and macrophage subsets.

Peyer's patches

Groups of lymphoid nodules present in the small intestine (usually the ileum). They occur in the intestinal wall, opposite the line of attachment of the mesentery. They consist of a dome area, B cell follicles and interfollicular T cell areas. High endothelial venules are present mainly in the interfollicular areas.

Mesenteric lymph nodes

Lymph nodes, located at the base of the mesentery, that collect lymph (including cells and antigens) draining from the intestinal mucosa.

Microfold cells

(M cells). Specialized antigen-sampling cells that are located in the follicle-associated epithelium of the organized mucosa-associated lymphoid tissues. M cells deliver antigens by transepithelial vesicular transport from the aero-digestive lumen directly to subepithelial lymphoid tissues of nasopharynx-associated lymphoid tissue and Peyer's patches.

NKG2D

(Natural killer group 2, member D). A lectin-type activating receptor that is encoded by the NK complex and is expressed at the surface of NK cells, NKT cells, natural and induced intraepithelial lymphocytes and conventional T cell receptor-γδ (TCRγδ) T cells, as well as some conventional cytolytic CD8αβ+TCRαβ+ T cells. The ligands for NKG2D are MHC class I polypeptide-related sequence A (MICA) and MICB in humans, and retinoic acid early transcript 1 (RAE1) and H60 in mice. Such ligands are generally expressed at the surface of infected, stressed or transformed cells.

Inflammatory bowel disease

A chronic condition of the intestine that is characterized by severe inflammation and mucosal tissue destruction. The most common forms in humans are ulcerative colitis and Crohn's disease.

Coeliac disease

Coeliac disease is a condition that damages the lining of the small intestine and interferes with nutrient absorption. The damage is due to an aberrant immune response to gluten-derived antigens, which are found in wheat, barley, rye and possibly oats.

Crohn's disease

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation, and it is thought to result from an abnormal T cell-mediated immune response to commensal bacteria.

Ulcerative colitis

A chronic disease that is characterized by inflammation of the mucosa and sub-mucosa tissues, mainly of the large intestine.

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Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol 11, 445–456 (2011). https://doi.org/10.1038/nri3007

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