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Diverse developmental pathways of intestinal intraepithelial lymphocytes

Nature Reviews Immunology volume 18, pages 514–525 (2018)Cite this article

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Abstract

The intestinal epithelial barrier is patrolled by resident intraepithelial lymphocytes (IELs) that are involved in host defence against pathogens, wound repair and homeostatic interactions with the epithelium, microbiota and nutrients. Intestinal IELs are one of the largest populations of lymphocytes in the body and comprise several distinct subsets, the identity and lineage relationships of which have long remained elusive. Here, we review advances in unravelling the complexity of intestinal IEL populations, which comprise conventional αβ T cell receptor (TCRαβ)+ subsets, unconventional TCRαβ+ and TCRγδ+ subsets, group 1 innate lymphoid cells (ILC1s) and ILC1-like cells. Although these intestinal IEL lineages have partially overlapping effector programmes and recognition properties, they have strikingly different developmental pathways. We suggest that evolutionary pressure has driven the recurrent generation of cytolytic effector lymphocytes to protect the intestinal epithelial layer, but they may also precipitate intestinal inflammatory disorders, such as coeliac disease.

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Fig. 1: Multiple pathways for the development of intestinal IEL lineages.
Fig. 2: Stereotypic functions of intestinal IEL lineages.

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Acknowledgements

The authors thank J. J. Bunker, S. A. Erickson and T. Mayassi for discussions and collaborations. B.D.M. is supported by the University of Chicago Physician Scientist Development Program. These studies were supported by US National Institutes of Health (NIH) grants RO1-AI038339 and UO1-AI125250 (A.B.) and RO1-DK067180 and RO1-DK100619 (B.J.) and by Digestive Diseases Research Core Center grant P30-DK42086.

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Authors and Affiliations

  1. Committee on Immunology, University of Chicago, Chicago, IL, USA

    Benjamin D. McDonald, Bana Jabri & Albert Bendelac

  2. Department of Pathology, University of Chicago, Chicago, IL, USA

    Benjamin D. McDonald, Bana Jabri & Albert Bendelac

  3. Department of Medicine, University of Chicago, Chicago, IL, USA

    Benjamin D. McDonald & Bana Jabri

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  1. Benjamin D. McDonald
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B.D.M. and A.B. were responsible for researching, writing, reviewing and editing the manuscript. B.J. made a substantial contribution to the discussion of content.

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Correspondence to Albert Bendelac.

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Glossary

CD8αα

A homodimer of CD8α molecules (in contrast to the CD8αβ heterodimer found on conventional CD8+ T cells) that is expressed by most intestinal intraepithelial lymphocytes; its function is not known, although it is known to bind the MHC class Ib molecule thymus leukaemia antigen (TL).

Innate lymphoid cells

(ILCs). Cells that develop from a common lymphoid progenitor but do not express lineage markers associated with other lymphocytes, such as recombined antigen receptors. These cells rapidly secrete effector cytokines in response to activation and have been subdivided into three main groups on the basis of whether they produce T helper 1 (TH1) cell-type, TH2 cell-type or TH17 cell-type cytokines.

Peyer’s patches

Highly specialized lymph node-like structures found on the anti-mesenteric side of the small intestine. They orchestrate immune responses against luminal antigens taken up by M cells.

Aryl hydrocarbon receptor

(AHR). A ligand-dependent transcription factor that is activated by dietary and microbial metabolites and that regulates the development of most intestinal intraepithelial lymphocytes.

αGalCer–CD1d tetramers

Tetrameric forms of CD1d molecules bound to α-galactosylceramide (αGalCer) that have sufficient affinity for the T cell receptor of natural killer T (NKT) cells to allow the detection of NKT cells by flow cytometry.

Refractory sprue

Pathological changes of the small intestine, including crypt hyperplasia and villous atrophy, that do not resolve in patients with coeliac disease on a gluten-free diet.

Mucosa-associated invariant T (MAIT) cells

A population of T cells with a semi-invariant αβ T cell receptor that recognizes riboflavin metabolites presented by the non-classical MHC class I molecule MHC class I-related gene protein (MR1).

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McDonald, B.D., Jabri, B. & Bendelac, A. Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat Rev Immunol 18, 514–525 (2018). https://doi.org/10.1038/s41577-018-0013-7

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