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

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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SYMBIOTIC MICROBIOTA Article Open access 11 September 2023 GROUP 3 INNATE LYMPHOID CELLS IN INTESTINAL HEALTH AND DISEASE Article 11 March 2024 BUTYROPHILIN-LIKE 2 REGULATES SITE-SPECIFIC

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  Download references 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. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Laboratory of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, 92037, California, USA Hilde Cheroutre & Florence Lambolez * Laboratory of

Mucosal Immunology, The Rockefeller University, New York, 10065, New York, USA Daniel Mucida Authors * Hilde Cheroutre View author publications You can also search for this author inPubMed 

Google Scholar * Florence Lambolez View author publications You can also search for this author inPubMed Google Scholar * Daniel Mucida View author publications You can also search for this

author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Hilde Cheroutre or Daniel Mucida. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial

interests. RELATED LINKS RELATED LINKS FURTHER INFORMATION Hilde Cheroutre's homepage Daniel Mucida's homepage 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. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. _Nat Rev Immunol_ 11,

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