Review Article | Published:

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

Nature Reviews Gastroenterology & Hepatologyvolume 15pages637649 (2018) | Download Citation

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Mowat, A. M. & Agace, W. W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14, 667–685 (2014).

  2. 2.

    Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153 (2014).

  3. 3.

    Murphy, K. & Weaver, C. Janeway’s Immunobiology (Garland Science, 2016).

  4. 4.

    Ganusov, V. V. & De Boer, R. J. Do most lymphocytes in humans really reside in the gut? Trends Immunol. 28, 514–518 (2007).

  5. 5.

    Park, C. O. & Kupper, T. S. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat. Med. 21, 688–697 (2015).

  6. 6.

    Masopust, D. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).

  7. 7.

    Fan, X. & Rudensky, A. Y. Hallmarks of tissue-resident lymphocytes. Cell 164, 1198–1211 (2016).

  8. 8.

    Burzyn, D., Benoist, C. & Mathis, D. Regulatory T cells in nonlymphoid tissues. Nat. Immunol. 14, 1007–1013 (2013).

  9. 9.

    Sujino, T. et al. Tissue adaptation of regulatory and intraepithelial CD4+ T cells controls gut inflammation. Science 352, 1581–1586 (2016).

  10. 10.

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

  11. 11.

    Hoytema van Konijnenburg, D. P. et al. Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection. Cell 43, 383–384 (2017).

  12. 12.

    Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity 38, 769–781 (2013).

  13. 13.

    Simoni, Y. et al. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity 46, 148–161 (2017).

  14. 14.

    Spencer, J. et al. Changes in intraepithelial lymphocyte subpopulations in coeliac disease and enteropathy associated T cell lymphoma (malignant histiocytosis of the intestine). Gut 30, 339–346 (1989).

  15. 15.

    Leon, F. et al. Human small-intestinal epithelium contains functional natural killer lymphocytes. Gastroenterology 125, 345–356 (2003).

  16. 16.

    Rostami, K. et al. ROC-king onwards: intraepithelial lymphocyte counts, distribution and role in coeliac disease mucosal interpretation. Gut 66, 2080–2086 (2017).

  17. 17.

    Hirata, I., Berrebi, G., Austin, L. L., Keren, D. F. & Dobbins, W. O. Immunohistological characterization of intraepithelial and lamina propria lymphocytes in control ileum and colon and in inflammatory bowel disease. Dig. Dis. Sci. 31, 593–603 (1986).

  18. 18.

    Bednarska, O., Ignatova, S., Dahle, C. & Ström, M. Intraepithelial lymphocyte distribution differs between the bulb and the second part of duodenum. BMC Gastroenterol. 13, 111 (2013).

  19. 19.

    Austin, L. L. & Dobbins, W. O. Intraepithelial leukocytes of the intestinal mucosa in normal man and in Whipple’s disease: a light- and electron-microscopic study. Dig. Dis. Sci. 27, 311–320 (1982).

  20. 20.

    Ahn, J. Y. et al. Colonic mucosal immune activity in irritable bowel syndrome: comparison with healthy controls and patients with ulcerative colitis. Dig. Dis. Sci. 59, 1001–1011 (2014).

  21. 21.

    Faderl, M., Noti, M., Corazza, N. & Mueller, C. Keeping bugs in check: the mucus layer as a critical component in maintaining intestinal homeostasis. IUBMB Life 67, 275–285 (2015).

  22. 22.

    Hansson, G. C. Role of mucus layers in gut infection and inflammation. Curr. Opin. Microbiol. 15, 57–62 (2012).

  23. 23.

    Ruscher, R., Kummer, R. L., Lee, Y. J., Jameson, S. C. & Hogquist, K. A. CD8alphaalpha intraepithelial lymphocytes arise from two main thymic precursors. Nat. Immunol. 18, 771–779 (2017).

  24. 24.

    Klose, C. S. N. et al. A committed postselection precursor to natural TCRαβ+ intraepithelial lymphocytes. Mucosal Immunol. 11, 333–344 (2018).

  25. 25.

    van Wijk, F. & Cheroutre, H. Intestinal T cells: facing the mucosal immune dilemma with synergy and diversity. Seminars Immunol. 21, 130–138 (2009).

  26. 26.

    McVay, L. D., Jaswal, S. S., Kennedy, C., Hayday, A. & Carding, S. R. The generation of human gammadelta T cell repertoires during fetal development. J. Immunol. 160, 5851–5860 (1998).

  27. 27.

    Spencer, J., Isaacson, P. G., Walker-Smith, J. A. & MacDonald, T. T. Heterogeneity in intraepithelial lymphocyte subpopulations in fetal and postnatal human small intestine. J. Pediatr. Gastroenterol. Nutr. 9, 173–177 (1989).

  28. 28.

    Mold, J. E. et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330, 1695–1699 (2010).

  29. 29.

    Sathaliyawala, T. et al. Distribution and compartmentalization of human circulating and tissue-resident memory t cell subsets. Immunity 38, 187–197 (2013).

  30. 30.

    Thome, J. J. C. et al. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat. Med. 22, 72–77 (2016).

  31. 31.

    Jarry, A., Cerf-Bensussan, N., Brousse, N., Selz, F. & Guy-grand, D. Subsets of CD3+ (T cell receptor α/β or γ/δ) and CD3 lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur. J. Immunol. 20, 1097–1103 (1990).

  32. 32.

    Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).

  33. 33.

    Bakdash, G., Vogelpoel, L. T., van Capel, T. M., Kapsenberg, M. L. & de Jong, E. C. Retinoic acid primes human dendritic cells to induce gut-homing, IL-10-producing regulatory T cells. Mucosal Immunol. 8, 265–278 (2015).

  34. 34.

    Zabel, B. A. et al. Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J. Exp. Med. 190, 1241–1256 (1999).

  35. 35.

    Cerf-Bensussan, N., Bègue, B., Gagnon, J. & Meo, T. The human intraepithelial lymphocyte marker HML-1 is an integrin consisting of a β7 subunit associated with a distinctive α chain. Eur. J. Immunol. 22, 273–277 (1992).

  36. 36.

    Raine, T., Liu, J. Z., Anderson, C. A., Parkes, M. & Kaser, A. Generation of primary human intestinal T cell transcriptomes reveals differential expression at genetic risk loci for immune-mediated disease. Gut 64, 250–259 (2015).

  37. 37.

    Briskin, M. et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am. J. Pathol. 151, 97–110 (1997).

  38. 38.

    Habtezion, A., Nguyen, L. P., Hadeiba, H. & Butcher, E. C. Leukocyte trafficking to the small intestine and colon. Gastroenterology 150, 340–354 (2016).

  39. 39.

    Salmi, M. & Jalkanen, S. Lymphocyte homing to the gut: attraction, adhesion, and commitment. Immunol. Rev. 206, 100–113 (2005).

  40. 40.

    Dogan, A., Wang, Z. D. & Spencer, J. E-cadherin expression in intestinal epithelium. J. Clin. Pathol. 48, 143–146 (1995).

  41. 41.

    Kuklin, N. A. et al. Alpha4beta7 independent pathway for CD8+ T cell-mediated intestinal immunity to rotavirus. J. Clin. Invest. 106, 1541–1552 (2000).

  42. 42.

    Zundler, S. et al. The alpha4beta1 homing pathway is essential for ileal homing of Crohn’s disease effector T cells in vivo. Inflamm. Bowel Dis. 23, 379–391 (2017).

  43. 43.

    Di Marco Barros, R. et al. Epithelia use butyrophilin-like molecules to shape organ-specific gammadelta T cell compartments. Cell 167, 203–218 (2016).

  44. 44.

    Laidlaw, B. J. et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633–645 (2014).

  45. 45.

    Mackay, L. K. et al. The developmental pathway for CD103+CD8+tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).

  46. 46.

    Zhang, N. & Bevan, M. J. Transforming growth factor-beta signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39, 687–696 (2013).

  47. 47.

    Mackay, L. K. et al. T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate. Immunity 43, 1101–1111 (2015).

  48. 48.

    Mohammed, J. et al. Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β. Nat. Immunol. 17, 414–421 (2016).

  49. 49.

    Jiang, W. et al. Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J. Exp. Med. 210, 2465–2476 (2013).

  50. 50.

    Muzes, G., Molnar, B., Tulassay, Z. & Sipos, F. Changes of the cytokine profile in inflammatory bowel diseases. World J. Gastroenterol. 18, 5848–5861 (2012).

  51. 51.

    Park, J. H., Peyrin-Biroulet, L., Eisenhut, M. & Shin, J. Il. IBD immunopathogenesis: a comprehensive review of inflammatory molecules. Autoimmun. Rev. 16, 416–426 (2017).

  52. 52.

    Meresse, B. et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357–366 (2004).

  53. 53.

    Qiu, Y. et al. TLR2-dependent signaling for IL-15 production is essential for the homeostasis of intestinal intraepithelial lymphocytes. Mediators Inflamm. 2016, 4281865 (2016).

  54. 54.

    Lanier, L. L., Le, A. M., Civin, C. I., Loken, M. R. & Phillips, J. H. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J. Immunol. 136, 4480–4486 (1986).

  55. 55.

    Ohkawa, T. et al. Systematic characterization of human CD8+ T cells with natural killer cell markers in comparison with natural killer cells and normal CD8+ T cells. Immunology 103, 281–290 (2001).

  56. 56.

    Mucida, D. et al. Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat. Immunol. 14, 281–289 (2013).

  57. 57.

    Reis, B. S., Hoytema van Konijnenburg, D. P., Grivennikov, S. I. & Mucida, D. Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. Immunity 41, 244–256 (2014).

  58. 58.

    Sarrabayrouse, G. et al. CD4CD8αα lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease. PLOS Biol. 12, e1001833 (2014).

  59. 59.

    Dalton, J. E. et al. Intraepithelial gammadelta+lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection. Gastroenterology 131, 818–829 (2006).

  60. 60.

    Ismail, A. S., Behrendt, C. L. & Hooper, L. V. Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury. J. Immunol. 182, 3047–3054 (2009).

  61. 61.

    Edelblum, K. L. et al. gammadelta Intraepithelial lymphocyte migration limits transepithelial pathogen invasion and systemic disease in mice. Gastroenterology 148, 1417–1426 (2015).

  62. 62.

    Perera, L. et al. Expression of nonclassical class I molecules by intestinal epithelial cells. Inflamm. Bowel Dis. 13, 298–307 (2007).

  63. 63.

    Lin, X. P., Almqvist, N. & Telemo, E. Human small intestinal epithelial cells constitutively express the key elements for antigen processing and the production of exosomes. Blood Cells, Mol. Dis. 35, 122–128 (2005).

  64. 64.

    Strid, J., Sobolev, O., Zafirova, B., Polic, B. & Hayday, A. The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science 334, 1293–1297 (2011).

  65. 65.

    Vantourout, P. et al. Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway. Sci. Transl. Med. 6, 231ra49 (2014).

  66. 66.

    Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2, 997–1003 (2001).

  67. 67.

    Shires, J., Theodoridis, E. & Hayday, A. C. Biological insights into TCRγδ+ and TCRαβ+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 15, 419–434 (2001).

  68. 68.

    Deusch, K. et al. A major fraction of human intraepithelial lymphocytes simultaneously expresses the gamma/delta T cell receptor, the CD8 accessory molecule and preferentially uses the V delta 1 gene segment. Eur. J. Immunol. 21, 1053–1059 (1991).

  69. 69.

    Lundqvist, C. et al. Phenotype and cytokine profile of intraepithelial lymphocytes in human small and large intestine. Ann. NY Acad. Sci. 756, 395–399 (1995).

  70. 70.

    Lundqvist, C., Melgar, S., Yeung, M. M., Hammarström, S. & Hammarström, M. L. Intraepithelial lymphocytes in human gut have lytic potential and a cytokine profile that suggest T helper 1 and cytotoxic functions. J. Immunol. 157, 1926–1934 (1996).

  71. 71.

    Hoang, P., Crotty, B., Dalton, H. R. & Jewell, D. P. Epithelial cells bearing class II molecules stimulate allogeneic human colonic intraepithelial lymphocytes. Gut 33, 1089–1093 (1992).

  72. 72.

    Booth, J. S. et al. Characterization and functional properties of gastric tissue-resident memory T cells from children, adults, and the elderly. Front. Immunol. 5, 1–15 (2014).

  73. 73.

    Youakim, A. & Ahdieh, M. Interferon-gamma decreases barrier function in T84 cells by reducing ZO-1 levels and disrupting apical actin. Am. J. Physiol. 276, G1279–G1288 (1999).

  74. 74.

    Smyth, D., Leung, G., Fernando, M. & McKay, D. M. Reduced surface expression of epithelial E-cadherin evoked by interferon-gamma is Fyn kinase-dependent. PLOS One 7, e38441 (2012).

  75. 75.

    Qiu, Y. & Yang, H. Effects of intraepithelial lymphocyte-derived cytokines on intestinal mucosal barrier function. J. Interf. Cytokine Res. 33, 551–562 (2013).

  76. 76.

    Cerf-Bensussan, N., Guy-Grand, D. & Griscelli, C. Intraepithelial lymphocytes of human gut: isolation, characterisation and study of natural killer activity. Gut 26, 81–88 (1985).

  77. 77.

    Russell, G. J., Nagler-Anderson, C., Anderson, P. & Bhan, A. K. Cytotoxic potential of intraepithelial lymphocytes (IELs). Presence of TIA-1, the cytolytic granule-associated protein, in human IELs in normal and diseased intestine. Am. J. Pathol. 143, 350–354 (1993).

  78. 78.

    Dobbins, W. O. 3rd. Human intestinal intraepithelial lymphocytes. Gut 27, 972–985 (1986).

  79. 79.

    Chott, A. et al. Intraepithelial lymphocytes in normal human intestine do not express proteins associated with cytolytic function. Am. J. Pathol. 151, 435–442 (1997).

  80. 80.

    Di Sabatino, A. et al. Intraepithelial and lamina propria lymphocytes show distinct patterns of apoptosis whereas both populations are active in Fas based cytotoxicity in coeliac disease. Gut 49, 380–386 (2001).

  81. 81.

    Hongo, T. et al. Functional expression of Fas and Fas ligand on human colonic intraepithelial T lymphocytes. J. Int. Med. Res. 28, 132–142 (1999).

  82. 82.

    Raulet, D. H. Roles of the NKG2D immunoreceptor and its ligands. Nat. Rev. Immunol. 3, 781–790 (2003).

  83. 83.

    Colucci, F., Di Santo, J. P. & Leibson, P. J. Natural killer cell activation in mice and men: different triggers for similar weapons? Nat. Immunol. 3, 807–813 (2002).

  84. 84.

    Cheroutre, H. & Lambolez, F. Doubting the TCR coreceptor function of CD8αα. Immunity 28, 149–159 (2008).

  85. 85.

    Menezes, J. S. et al. Stimulation by food proteins plays a critical role in the maturation of the immune system. Int. Immunol. 15, 447–455 (2003).

  86. 86.

    Bandeira, A. et al. Localization of gamma/delta T cells to the intestinal epithelium is independent of normal microbial colonization. J. Exp. Med. 172, 239–244 (1990).

  87. 87.

    Finch, P. W., Pricolo, V., Wu, A. & Finkelstein, S. D. Increased expression of keratinocyte growth factor messenger RNA associated with inflammatory bowel disease. Gastroenterology 110, 441–451 (1996).

  88. 88.

    Finch, P. W. & Cheng, A. L. Analysis of the cellular basis of keratinocyte growth factor overexpression in inflammatory bowel disease. Gut 45, 848–855 (1999).

  89. 89.

    Rubin, J. S. et al. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc. Natl Acad. Sci. USA 86, 802–806 (1989).

  90. 90.

    Yang, H., Antony, P. A., Wildhaber, B. E. & Teitelbaum, D. H. Intestinal intraepithelial lymphocyte-T cell-derived keratinocyte growth factor modulates epithelial growth in the mouse. J. Immunol. 172, 4151–4158 (2004).

  91. 91.

    Sturm, A. & Dignass, A. U. Epithelial restitution and wound healing in inflammatory bowel disease. World J. Gastroenterol. 14, 348–353 (2008).

  92. 92.

    Sundin, J. et al. Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress. Aliment. Pharmacol. Ther. 41, 342–351 (2015).

  93. 93.

    Geva-Zatorsky, N. et al. Mining the human gut microbiota for immunomodulatory organisms. Cell 168, 928–943 (2017).

  94. 94.

    Umesaki, Y., Setoyama, H., Matsumoto, S. & Okada, Y. Expansion of axf T cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from thymus. Immunology 79, 32–37 (1993).

  95. 95.

    Semenkovich, N. P. et al. Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes. Proc. Natl Acad. Sci. USA 113, 201617793 (2016).

  96. 96.

    Park, J. et al. Short chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol. 8, 80–93 (2015).

  97. 97.

    Cabinian, A. et al. Gut symbiotic microbes imprint intestinal immune cells with the innate receptor SLAMF4 which contributes to gut immune protection against enteric pathogens. Gut 67, 847–859 (2018).

  98. 98.

    O’Keeffe, M. S. et al. SLAMF4 is a negative regulator of expansion of cytotoxic intraepithelial CD8+ T cells that maintains homeostasis in the small intestine. Gastroenterology 148, 991–1001 (2015).

  99. 99.

    Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

  100. 100.

    Hubbard, T. D. et al. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 5, 12689 (2015).

  101. 101.

    Julliard, W., Fechner, J. H. & Mezrich, J. D. The aryl hydrocarbon receptor meets immunology: Friend or foe? A little of both. Front. Immunol. 5, 458 (2014).

  102. 102.

    Ji, T. et al. Aryl hydrocarbon receptor activation down-regulates IL-7 and reduces inflammation in a mouse model of DSS-induced colitis. Dig. Dis. Sci. 60, 1958–1966 (2015).

  103. 103.

    Monteleone, I., Pallone, F. & Monteleone, G. Aryl hydrocarbon receptor and colitis. Semin. Immunopathol. 35, 671–675 (2013).

  104. 104.

    Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248 (2011).

  105. 105.

    Clark, R. A. Resident memory T cells in human health and disease. Sci. Transl Med. 7, 269rv1 (2015).

  106. 106.

    Rutgeerts, P. et al. Natural history of recurrent Crohn’s disease at the ileocolonic anastomosis after curative surgery. Gut 25, 665–672 (1984).

  107. 107.

    Pascua, M., Su, C., Lewis, J. D., Brensinger, C. & Lichtenstein, G. R. Meta-analysis: factors predicting post-operative recurrence with placebo therapy in patients with Crohn’s disease. Aliment. Pharmacol. Ther. 28, 545–556 (2008).

  108. 108.

    Brown, I., Mino-Kenudson, M., Deshpande, V. & Lauwers, G. Y. Intraepithelial lymphocytosis in architecturally preserved proximal small intestinal mucosa: an increasing diagnostic problem with a wide differential diagnosis. Arch. Pathol. Lab. Med. 130, 1020–1025 (2006).

  109. 109.

    Chang, F., Mahadeva, U. & Deere, H. Pathological and clinical significance of increased intraepithelial lymphocytes (IELs) in small bowel mucosa. APMIS 113, 385–399 (2005).

  110. 110.

    Shmidt, E., Smyrk, T. C., Faubion, W. A. & Oxentenko, A. S. Duodenal intraepithelial lymphocytosis with normal villous architecture in pediatric patients: Mayo Clinic experience, 2000–2009. J. Pediatr. Gastroenterol. Nutr. 56, 51–55 (2013).

  111. 111.

    Parihar, V. et al. Clinical outcome of patients with raised intraepithelial lymphocytes with normal villous architecture on duodenal biopsy. Digestion 95, 288–292 (2017).

  112. 112.

    Jabri, B. & Sollid, L. M. T. Cells in celiac disease. J. Immunol. 198, 3005–3014 (2017).

  113. 113.

    Green, P. H. R. & Cellier, C. Celiac disease. N. Engl. J. Med. 357, 1731–1743 (2007).

  114. 114.

    Meresse, B., Malamut, G. & Cerf-Bensussan, N. Celiac disease: an immunological jigsaw. Immunity 36, 907–919 (2012).

  115. 115.

    Abadie, V., Discepolo, V. & Jabri, B. Intraepithelial lymphocytes in celiac disease immunopathology. Semin. Immunopathol. 34, 551–556 (2012).

  116. 116.

    Goldstein, N. S. & Underhill, J. Morphologic features suggestive of gluten sensitivity in architecturally normal duodenal biopsy specimens. Am. J. Clin. Pathol. 116, 63–71 (2001).

  117. 117.

    Steenholt, J. V. et al. The composition of T cell subtypes in duodenal biopsies are altered in coeliac disease patients. PLOS One 12, 1–17 (2017).

  118. 118.

    Hue, S. et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367–377 (2004).

  119. 119.

    Allegretti, Y. L. et al. Broad MICA/B expression in the small bowel mucosa: a link between cellular stress and celiac disease. PLOS One 8, e73658 (2013).

  120. 120.

    Fehniger, T. A. & Caligiuri, M. A. Interleukin 15: biology and relevance to human disease. Blood 97, 14–32 (2001).

  121. 121.

    Jabri, B. et al. Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology 118, 867–879 (2000).

  122. 122.

    Setty, M. et al. Distinct and synergistic contributions of epithelial stress and adaptive immunity to functions of intraepithelial killer cells and active celiac disease. Gastroenterology 149, 681–691 (2015).

  123. 123.

    Tang, F. et al. Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15. J. Exp. Med. 206, 707–719 (2009).

  124. 124.

    Tang, F. et al. Cysteinyl leukotrienes mediate lymphokine killer activity induced by NKG2D and IL-15 in cytotoxic T cells during celiac disease. J. Exp. Med. 212, 1487–1495 (2015).

  125. 125.

    Sarra, M. et al. IL-15 positively regulates IL-21 production in celiac disease mucosa. Mucosal Immunol. 6, 244–255 (2013).

  126. 126.

    Ebert, E. C. Interleukin 21 up-regulates perforin-mediated cytotoxic activity of human intra-epithelial lymphocytes. Immunology 127, 206–215 (2009).

  127. 127.

    Ciccocioppo, R. et al. Cytolytic mechanisms of intraepithelial lymphocytes in coeliac disease (CoD). Clin. Exp. Immunol. 120, 235–240 (2000).

  128. 128.

    Long, E. O. et al. Killer cell inhibitory receptors: diversity, specificity, and function. Immunol. Rev. 155, 135–144 (1997).

  129. 129.

    Tuire, I. et al. Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease. Am. J. Gastroenterol. 107, 1563–1569 (2012).

  130. 130.

    Kutlu, T. et al. Numbers of T cell receptor (TCR) alpha beta+but not of TCR gamma delta+intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut 34, 208–214 (1993).

  131. 131.

    Järvinen, T. T. et al. Intraepithelial lymphocytes in celiac disease. Am. J. Gastroenterol. 98, 1332–1337 (2003).

  132. 132.

    Chen, Y., Chou, K., Fuchs, E., Havran, W. L. & Boismenu, R. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc. Natl Acad. Sci. USA 99, 14338–14343 (2002).

  133. 133.

    Fiocchi, C., Battisto, J. R. & Farmer, R. G. Gut mucosal lymphocytes in inflammatory bowel disease: isolation and preliminary functional characterization. Dig. Dis. Sci. 24, 705–717 (1979).

  134. 134.

    Walker, M. M. et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment. Pharmacol. Ther. 29, 765–773 (2009).

  135. 135.

    Posnett, D. N. et al. T cell antigen receptor V gene usage. Increases in V beta 8+T cells in Crohn’s disease. J. Clin. Invest. 85, 1770–1776 (1990).

  136. 136.

    Mitomi, H. et al. Contribution of TIA-1+ and granzyme B+ cytotoxic T lymphocytes to cryptal apoptosis and ulceration in active inflammatory bowel disease. Pathol. Res. Pract. 203, 717–723 (2007).

  137. 137.

    Hardee, S., Alper, A., Pashankar, D. S. & Morotti, R. A. Histopathology of duodenal mucosal lesions in pediatric patients with inflammatory bowel disease: statistical analysis to identify distinctive features. Pediatr. Dev. Pathol. 17, 450–454 (2014).

  138. 138.

    Trejdosiewicz, L. K. et al. Gamma delta T cell receptor-positive cells of the human gastrointestinal mucosa: occurrence and V region gene expression in Heliobacter pylori-associated gastritis, coeliac disease and inflammatory bowel disease. Clin. Exp. Immunol. 84, 440–444 (1991).

  139. 139.

    Cuvelier, C. A., Wever, N. D. E., Mielants, H., Vos, M. D. E. & Veyst, E. M. Expression of T cell receptors patients with Crohn’s disease and with spondylarthropathy. Clin. Exp. Immunol. 90, 275–279 (1992).

  140. 140.

    Vidali, F. et al. Increased CD8+ intraepithelial lymphocyte infiltration and reduced surface area to volume ratio in the duodenum of patients with ulcerative colitis. Scand. J. Gastroenterol. 45, 684–689 (2010).

  141. 141.

    Nüssler, N. C. et al. Enhanced cytolytic activity of intestinal intraepithelial lymphocytes in patients with Crohn’s disease. Langenbecks. Arch. Surg. 385, 218–224 (2000).

  142. 142.

    Liu, Z. et al. The increased expression of IL-23 in inflammatory bowel disease promotes intraepithelial and lamina propria lymphocyte inflammatory responses and cytotoxicity. J. Leukoc. Biol. 89, 597–606 (2011).

  143. 143.

    Allez, M. et al. CD4+NKG2D+T cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions. Gastroenterology 132, 2346–2358 (2007).

  144. 144.

    Silva, F. A. R., Rodrigues, B. L., Ayrizono, M., de, L. S. & Leal, R. F. The immunological basis of inflammatory bowel disease. Gastroenterol. Res. Pract. 2016, 2097274 (2016).

  145. 145.

    Hendrickson, B. A., Gokhale, R. & Cho, J. H. Clinical aspects and pathophysiology of inflammatory bowel disease. Clin. Microbiol. Rev. 15, 79–94 (2002).

  146. 146.

    Rutter, M. et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126, 451–459 (2004).

  147. 147.

    Gupta, R. B. et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 133, 1091–1099 (2007).

  148. 148.

    Ullman, T. A. & Itzkowitz, S. H. Intestinal inflammation and cancer. Gastroenterology 140, 1807–1816 (2011).

  149. 149.

    Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

  150. 150.

    Chirica, M. et al. Phenotypic analysis of T cells infiltrating colon cancers: Correlations with oncogenetic status. Oncoimmunology 4, e1016698 (2015).

  151. 151.

    Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

  152. 152.

    Sherwood, A. M. et al. Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue. Cancer Immunol. Immunother. 62, 1453–1461 (2013).

  153. 153.

    Maeurer, M. J. et al. Human intestinal Vdelta1+lymphocytes recognize tumor cells of epithelial origin. J. Exp. Med. 183, 1681–1696 (1996).

  154. 154.

    Ebert, E. C. & Groh, V. Dissection of spontaneous cytotoxicity by human intestinal intraepithelial lymphocytes: MIC on colon cancer triggers NKG2D-mediated lysis through Fas ligand. Immunology 124, 33–41 (2008).

  155. 155.

    Dewar, D. H. et al. Celiac disease: management of persistent symptoms in patients on a gluten-free diet. World J. Gastroenterol. 18, 1348–1356 (2012).

  156. 156.

    Yokoyama, S. et al. Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes. Proc. Natl Acad. Sci. USA 106, 15849–15854 (2009).

  157. 157.

    US National Library of Medicine. Clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT02637141 (2018).

  158. 158.

    Jabri, B. & Abadie, V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat. Rev. Immunol. 15, 771–783 (2015).

  159. 159.

    Gomollon, F. et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: Part 1: Diagnosis and medical management. J. Crohns. Colitis 11, 3–25 (2017).

  160. 160.

    Terdiman, J. P., Gruss, C. B., Heidelbaugh, J. J., Sultan, S. & Falck-Ytter, Y. T. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology 145, 1459–1463 (2013).

  161. 161.

    American Gastroenterological Association. Crohns disease clinical care pathway. Available at: http://campaigns.gastro.org/algorithms/IBDCarePathway/pdf/IBDCarePathway.pdf. (Accessed: 7th November 2017).

  162. 162.

    Peyrin-Biroulet, L. & Lemann, M. Review article: remission rates achievable by current therapies for inflammatory bowel disease. Aliment. Pharmacol. Ther. 33, 870–879 (2011).

  163. 163.

    Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N. Engl. J. Med. 369, 711–721 (2013).

  164. 164.

    Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699–710 (2013).

  165. 165.

    Vermeire, S. et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 384, 309–318 (2014).

  166. 166.

    Wyant, T., Yang, L. & Fedyk, E. In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes. MAbs 5, 842–850 (2013).

  167. 167.

    Fischer, A. et al. Differential effects of alpha4beta7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut 65, 1642–1664 (2016).

  168. 168.

    Wang, C. et al. Effect of α4β7 blockade on intestinal lymphocyte subsets and lymphoid tissue development. Inflamm. Bowel Dis. 16, 1751–1762 (2010).

  169. 169.

    Lissner, D. et al. P617 Extraintestinal autoimmune phenomena during treatment with vedolizumab. J. Crohns Colitis 11, S394–S395 (2017).

  170. 170.

    Loftus, E. V. et al. Long-term effectiveness and safety of vedolizumab in patients with ulcerative colitis: 5-year cumulative exposure of GEMINI 1 completers rolling into the GEMINI open-label extension study. J. Crohns Colitis 11, S182–S183 (2017).

  171. 171.

    Wagner, N. et al. Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature 382, 366–370 (1996).

  172. 172.

    Nguyen, L. P. et al. Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nat. Immunol. 16, 207–213 (2015).

  173. 173.

    Ho, J. et al. A CD8+/CD103high T cell subset regulates TNF-mediated chronic murine ileitis. J. Immunol. 180, 2573–2580 (2008).

  174. 174.

    Mestas, J. & Hughes, C. C. W. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

  175. 175.

    Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

  176. 176.

    Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).

  177. 177.

    Dutronc, Y. & Porcelli, S. A. The CD1 family and T cell recognition of lipid antigens. Tissue Antigens 60, 337–353 (2002).

  178. 178.

    Wyer, J. R. et al. T cell receptor and coreceptor CD8 alphaalpha bind peptide-MHC independently and with distinct kinetics. Immunity 10, 219–225 (1999).

  179. 179.

    Cawthon, A. G., Lu, H. & Alexander-Miller, M. A. Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8alphabeta versus CD8alphaalpha expression. J. Immunol. 167, 2577–2584 (2001).

  180. 180.

    Srour, E. F., Leemhuis, T., Jenski, L., Redmond, R. & Jansen, J. Cytolytic activity of human natural killer cell subpopulations isolated by four-color immunofluorescence flow cytometric cell sorting. Cytometry 11, 442–446 (1990).

  181. 181.

    van den Broek, T., Borghans, J. A. M. & van Wijk, F. The full spectrum of human naive T cells. Nat. Rev. Immunol. 18, 363–373 (2018).

  182. 182.

    Thome, J. J. C. et al. Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, eaah6506 (2016).

  183. 183.

    Deusch, K. et al. Lymphokine repertoire and proliferative capacity of human intestinal intraepithelial lymphocytes. Gastroenterology 100, A574 (1991).

  184. 184.

    Cerf-Bensussan, N. et al. A monoclonal antibody (HML-1) defining a novel membrane molecule present on human intestinal lymphocytes. Eur. J. Immunol. 17, 1279–1285 (1987).

  185. 185.

    Bhagat, G. et al. Small intestinal CD8+TCRγδ+NKG2A+intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. J. Clin. Investig. 118, 281–293 (2008).

Download references

Acknowledgements

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.

Reviewer information

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

Author information

Affiliations

  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

Authors

  1. Search for Lisanne Lutter in:

  2. Search for David P. Hoytema van Konijnenburg in:

  3. Search for Eelco C. Brand in:

  4. Search for Bas Oldenburg in:

  5. Search for Femke van Wijk in:

Contributions

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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Femke van Wijk.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41575-018-0039-0