Intraepithelial Lymphocytes of the Intestine

Overview

Journal Annu Rev Immunol

Specialty Allergy & Immunology

Date 2024 Jan 26

PMID 38277691

Authors

Ainsley Lockhart

Daniel Mucida

Angelina M Bilate

Affiliations

Soon will be listed here.

Abstract

The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer.

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References

London M, Bilate A, Castro T, Sujino T, Mucida D . Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program. Nat Immunol. 2021; 22(4):449-459. PMC: 8251700. DOI: 10.1038/s41590-021-00883-8. View

Bilate A, Bousbaine D, Mesin L, Agudelo M, Leube J, Kratzert A . Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor. Sci Immunol. 2017; 1(2):eaaf7471. PMC: 6296461. DOI: 10.1126/sciimmunol.aaf7471. View

Torow N, Yu K, Hassani K, Freitag J, Schulz O, Basic M . Active suppression of intestinal CD4(+)TCRαβ(+) T-lymphocyte maturation during the postnatal period. Nat Commun. 2015; 6:7725. PMC: 4518322. DOI: 10.1038/ncomms8725. View

Sethna Z, Elhanati Y, Dudgeon C, Callan Jr C, Levine A, Mora T . Insights into immune system development and function from mouse T-cell repertoires. Proc Natl Acad Sci U S A. 2017; 114(9):2253-2258. PMC: 5338539. DOI: 10.1073/pnas.1700241114. View

Masopust D, Jiang J, Shen H, Lefrancois L . Direct analysis of the dynamics of the intestinal mucosa CD8 T cell response to systemic virus infection. J Immunol. 2001; 166(4):2348-56. DOI: 10.4049/jimmunol.166.4.2348. View

Mengel J, Cardillo F, Aroeira L, Williams O, Russo M, Vaz N . Anti-gamma delta T cell antibody blocks the induction and maintenance of oral tolerance to ovalbumin in mice. Immunol Lett. 1995; 48(2):97-102. DOI: 10.1016/0165-2478(95)02451-4. View

Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N . Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011; 34(2):237-46. DOI: 10.1016/j.immuni.2011.01.016. View

Helgeland L, Johansen F, Utgaard J, Vaage J, Brandtzaeg P . Oligoclonality of rat intestinal intraepithelial T lymphocytes: overlapping TCR beta-chain repertoires in the CD4 single-positive and CD4/CD8 double-positive subsets. J Immunol. 1999; 162(5):2683-92. View

Gebhardt T, Wakim L, Eidsmo L, Reading P, Heath W, Carbone F . Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol. 2009; 10(5):524-30. DOI: 10.1038/ni.1718. View

10.

Tsuchiya T, Fukuda S, Hamada H, Nakamura A, Kohama Y, Ishikawa H . Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J Immunol. 2003; 171(10):5507-13. DOI: 10.4049/jimmunol.171.10.5507. View

11.

Basu J, Reis B, Peri S, Zha J, Hua X, Ge L . Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4 T cell identity and function. Nat Immunol. 2021; 22(8):969-982. PMC: 8887595. DOI: 10.1038/s41590-021-00980-8. View

12.

Christophersen A, Raki M, Bergseng E, Lundin K, Jahnsen J, Sollid L . Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge. United European Gastroenterol J. 2014; 2(4):268-78. PMC: 4114117. DOI: 10.1177/2050640614540154. View

13.

Crowl J, Heeg M, Ferry A, Milner J, Omilusik K, Toma C . Tissue-resident memory CD8 T cells possess unique transcriptional, epigenetic and functional adaptations to different tissue environments. Nat Immunol. 2022; 23(7):1121-1131. PMC: 10041538. DOI: 10.1038/s41590-022-01229-8. View

14.

Leishman A, Naidenko O, Attinger A, Koning F, Lena C, Xiong Y . T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule, TL. Science. 2001; 294(5548):1936-9. DOI: 10.1126/science.1063564. View

15.

Hendricks D, Fink P . Uneven colonization of the lymphoid periphery by T cells that undergo early TCR{alpha} rearrangements. J Immunol. 2009; 182(7):4267-74. PMC: 2709763. DOI: 10.4049/jimmunol.0804180. View

16.

Edelblum K, Singh G, Odenwald M, Lingaraju A, El Bissati K, McLeod R . γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice. Gastroenterology. 2015; 148(7):1417-26. PMC: 4685713. DOI: 10.1053/j.gastro.2015.02.053. View

17.

Gapin L, Cheroutre H, Kronenberg M . Cutting edge: TCR alpha beta+ CD8 alpha alpha+ T cells are found in intestinal intraepithelial lymphocytes of mice that lack classical MHC class I molecules. J Immunol. 1999; 163(8):4100-4. View

18.

Ferguson A . Intraepithelial lymphocytes of the small intestine. Gut. 1977; 18(11):921-37. PMC: 1411743. DOI: 10.1136/gut.18.11.921. View

19.

Vandereyken M, James O, Swamy M . Mechanisms of activation of innate-like intraepithelial T lymphocytes. Mucosal Immunol. 2020; 13(5):721-731. PMC: 7434593. DOI: 10.1038/s41385-020-0294-6. View

20.

Zmora N, Suez J, Elinav E . You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2018; 16(1):35-56. DOI: 10.1038/s41575-018-0061-2. View