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The elusive case of human intraepithelial T cells in gut homeostasis and inflammation

Nature Reviews Gastroenterology & Hepatology (2018) | Download Citation


The epithelial barrier of the gastrointestinal tract is home to numerous intraepithelial T cells (IETs). IETs are functionally adapted to the mucosal environment and are among the first adaptive immune cells to encounter microbial and dietary antigens. They possess hallmark features of tissue-resident T cells: they are long-lived nonmigratory cells capable of rapidly responding to antigen challenges independent of T cell recruitment from the periphery. Gut-resident T cells have been implicated in the relapsing and remitting course and persisting low-grade inflammation of chronic gastrointestinal diseases, including IBD and coeliac disease. So far, most data IETs have been derived from experimental animal models; however, IETs and the environmental makeup differ between mice and humans. With advances in techniques, the number of human studies has grown exponentially in the past 5 years. Here, we review the literature on the involvement of human IETs in gut homeostasis and inflammation, and how these cells are influenced by the microbiota and dietary antigens. Finally, targeting of IETs in therapeutic interventions is discussed. Broad insight into the function and role of human IETs in gut homeostasis and inflammation is essential to identify future diagnostic, prognostic and therapeutic strategies.

Key points

  • Intraepithelial T cells (IETs), residing at the epithelial barrier in the gastrointestinal tract, are an epitome of tissue-resident T cells.

  • Tissue-resident T cells are long-lived, nonrecirculating T cells that provide rapid immune responses independent of peripheral T cell recruitment.

  • IETs have an important role in immunosurveillance while simultaneously inducing tolerance for nonpathogenic antigens, consequently preserving the integrity of the single-layer epithelial membrane.

  • IBD and coeliac disease are characterized by a predominance of (recurrent) gastrointestinal inflammation.

  • The longevity and abundant presence of IETs at the intestinal epithelial barrier suggest a role for IETs in the relapsing and remitting course and persisting low-grade inflammation of these diseases.

  • As tissue-specific and potentially pathogenic cells, IETs are an ideal target for therapeutic (non-systemic) intervention in chronic, tissue-specific inflammatory diseases such as IBD.

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The authors apologize to those colleagues whose relevant work was not included in this Review owing to space constraints. The authors thank J. ten Hove for critically reading the manuscript and for helpful comments. F.v.W. is supported by a VIDI career development grant (016.146.332) from The Netherlands Organization for Health Research and Development (ZonMw). D.P.H.v.K. and E.C.B. are supported by the Alexandre Suerman programme for MD and PhD students of the University Medical Center Utrecht, Netherlands.

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Nature Reviews Gastroenterology & Hepatology thanks H. Cheroutre and other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Laboratory of Translational Immunology, Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, Netherlands

    • Lisanne Lutter
    • , David P. Hoytema van Konijnenburg
    • , Eelco C. Brand
    •  & Femke van Wijk
  2. Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, Netherlands

    • Lisanne Lutter
    • , Eelco C. Brand
    •  & Bas Oldenburg
  3. Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA

    • David P. Hoytema van Konijnenburg


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F.v.W. contributed to discussion of content and writing, reviewing and editing the manuscript. L.L. and D.P.H.v.K. contributed to all aspects of preparation of the manuscript. E.C.B. researched data and contributed to discussion of content and reviewing and editing the manuscript. B.O. contributed to discussion of content and reviewing and editing the manuscript.

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The authors declare no competing interests.

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Correspondence to Femke van Wijk.

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