Advertisement

Current Gastroenterology Reports

, Volume 12, Issue 6, pp 513–521 | Cite as

Intraepithelial Lymphocytes: To Serve and Protect

  • Brian S. Sheridan
  • Leo LefrançoisEmail author
Article

Abstract

The mucosal immune system is constantly exposed to a wide range of commensal and potentially pathogenic microbial species. Chronic exposure to foreign organisms makes generation of an appropriate immune response critical in maintaining a balance between elimination of harmful pathogens, peaceful coexistence with commensals, and prevention of autoimmunity. Intestinal intraepithelial lymphocytes provide a first line of defense at this extensive barrier with the outside world, and as such, understanding their role in immunity is critical.

Keywords

Mucosal immunology Intraepithelial lymphocyte CD8αβ T cell γδ T cell T-cell migration Immunologic memory Intestinal homeostasis Microbial surveillance 

Notes

Disclosure

Conflicts of interest: Dr. Sheridan’s institution has received grants from the Crohn’s and Colitis Foundation of America. Dr. Lefrançois’s laboratory has received grants from the National Institutes of Health.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Beagley KW, Fujihashi K, Lagoo AS, et al.: Differences in intraepithelial lymphocyte t cell subsets isolated from murine small versus large intestine. J Immunol 1995, 154:5611–5619.PubMedGoogle Scholar
  2. 2.
    Mysorekar IU, Lorenz RG, Gordon JI: A gnotobiotic transgenic mouse model for studying interactions between small intestinal enterocytes and intraepithelial lymphocytes. J Biol Chem 2002, 277:37811–37819.CrossRefPubMedGoogle Scholar
  3. 3.
    Spencer J, Isaacson PG, Macdonald TT, et al.: Gamma/delta T cells and the diagnosis of coeliac disease. Clin Exp Immunol 1991, 85:109–113.CrossRefPubMedGoogle Scholar
  4. 4.
    Leishman AJ, Naidenko OV, Attinger A, et al.: T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule, TL. Science 2001, 294:1936–1939.CrossRefPubMedGoogle Scholar
  5. 5.
    Pardigon N, Darche S, Kelsall B, et al.: The TL MHC class Ib molecule has only marginal effects on the activation, survival and trafficking of mouse small intestinal intraepithelial lymphocytes. Int Immunol 2004, 16:1305–1313.CrossRefPubMedGoogle Scholar
  6. 6.
    Cawthon AG, Lu H, Alexander-Miller MA: Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8alphabeta versus CD8alphaalpha expression. J Immunol 2001, 167:2577–2584.PubMedGoogle Scholar
  7. 7.
    Klonowski KD, Williams KJ, Marzo AL, et al.: Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 2004, 20:551–562.CrossRefPubMedGoogle Scholar
  8. 8.
    Lefrancois L, Goodman T: In vivo modulation of cytolytic activity and Thy-1 expression in TCR-gamma delta+ intraepithelial lymphocytes. Science 1989, 243:1716–1718.CrossRefPubMedGoogle Scholar
  9. 9.
    Masopust D, Vezys V, Wherry EJ, et al.: Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J Immunol 2006, 176:2079–2083.PubMedGoogle Scholar
  10. 10.
    Hamada S, Umemura M, Shiono T, et al.: IL-17A produced by gamma delta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver. J Immunol 2008, 181:3456–3463.PubMedGoogle Scholar
  11. 11.
    Sutton CE, Lalor SJ, Sweeney CM, et al.: Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009, 31:331–341.CrossRefPubMedGoogle Scholar
  12. 12.
    Martin B, Hirota K, Cua DJ, et al.: Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 2009, 31:321–330.CrossRefPubMedGoogle Scholar
  13. 13.
    Rhodes KA, Andrew EM, Newton DJ, et al.: A subset of IL-10-producing gammadelta T cells protect the liver from Listeria-elicited, CD8(+) T cell-mediated injury. Eur J Immunol 2008, 38:2274–2283.CrossRefPubMedGoogle Scholar
  14. 14.
    Chen Y, Chou K, Fuchs E, et al.: Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci U S A 2002, 99:14338–14343.CrossRefPubMedGoogle Scholar
  15. 15.
    Boismenu R, Havran WL: Modulation of epithelial cell growth by intraepithelial γδ T cells. Science 1994, 266:1253–1255.CrossRefPubMedGoogle Scholar
  16. 16.
    Kamanaka M, Kim ST, Wan YY, et al.: Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 2006, 25:941–952.CrossRefPubMedGoogle Scholar
  17. 17.
    Yang H, Antony PA, Wildhaber BE, Teitelbaum DH: Intestinal intraepithelial lymphocyte gamma delta-T cell-derived keratinocyte growth factor modulates epithelial growth in the mouse. J Immunol 2004, 172:4151–4158.PubMedGoogle Scholar
  18. 18.
    Groh V, Steinle A, Bauer S, Spies T: Recognition of stress-induced MHC molecules by intestinal epithelial γδ cells. Science 1999, 279:1737–1740.CrossRefGoogle Scholar
  19. 19.
    Yu Q, Tang C, Xun S, et al.: MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8 alpha alpha TCR alpha beta and TCR gamma delta intestinal intraepithelial lymphocytes. J Immunol 2006, 176:6180–6185.PubMedGoogle Scholar
  20. 20.
    Moretto M, Durell B, Schwartzman JD, Khan IA: Gamma delta T cell-deficient mice have a down-regulated CD8+ T cell immune response against Encephalitozoon cuniculi infection. J Immunol 2001, 166:7389–7397.PubMedGoogle Scholar
  21. 21.
    Roberts SJ, Smith AL, West AB, et al.: T-cell αβ+ and γδ+ deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proc Natl Acad Sci U S A 1996, 93:11774–11779.CrossRefPubMedGoogle Scholar
  22. 22.
    Inagaki-Ohara K, Dewi FN, Hisaeda H, et al.: Intestinal intraepithelial lymphocytes sustain the epithelial barrier function against Eimeria vermiformis infection. Infect Immun 2006, 74:5292–5301.CrossRefPubMedGoogle Scholar
  23. 23.
    Dalton JE, Cruickshank SM, Egan CE, et al.: Intraepithelial gammadelta+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection. Gastroenterology 2006, 131:818–829.CrossRefPubMedGoogle Scholar
  24. 24.
    Moretto M, Weiss LM, Khan IA: Induction of a rapid and strong antigen-specific intraepithelial lymphocyte response during oral Encephalitozoon cuniculi infection. J Immunol 2004, 172:4402–4409.PubMedGoogle Scholar
  25. 25.
    Suzuki H, Jeong K, Doi K: Age-related changes in the regional variations in the number and subsets of intraepithelial lymphocytes in mouse small intestine. Dev Comp Immunol 2002, 26:589–595.CrossRefPubMedGoogle Scholar
  26. 26.
    Masopust D, Vezys V, Marzo AL, Lefrançois L: Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001, 291:2413–2417.CrossRefPubMedGoogle Scholar
  27. 27.
    Agace W: Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol Lett 2010, 128:21–23.CrossRefPubMedGoogle Scholar
  28. 28.
    Iwasaki A, Kelsall BL: Unique functions of CD11b+, CD8α+, and double-negative Peyer’s patch dendritic cells. J Immunol 2001, 166:4884–4890.PubMedGoogle Scholar
  29. 29.
    Johansson C, Kelsall BL: Phenotype and function of intestinal dendritic cells. Semin Immunol 2005, 17:284–294.CrossRefPubMedGoogle Scholar
  30. 30.
    Salazar-Gonzalez RM, Niess JH, Zammit DJ, et al.: CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer’s patches. Immunity 2006, 24:623–632.CrossRefPubMedGoogle Scholar
  31. 31.
    Mora JR, Cheng G, Picarella D, et al.: Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J Exp Med 2005, 201:303–316.CrossRefPubMedGoogle Scholar
  32. 32.
    Iwata M, Hirakiyama A, Eshima Y, et al.: Retinoic acid imprints gut-homing specificity on T cells. Immunity 2004, 21:527–538.CrossRefPubMedGoogle Scholar
  33. 33.
    Svensson M, Johansson-Lindbom B, Zapata F, et al.: Retinoic acid receptor signaling levels and antigen dose regulate gut homing receptor expression on CD8+ T cells. Mucosal Immunol 2008, 1:38–48.CrossRefPubMedGoogle Scholar
  34. 34.
    Edele F, Molenaar R, Gutle D, et al.: Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns. J Immunol 2008, 181:3745–3749.PubMedGoogle Scholar
  35. 35.
    Masopust D, Choo D, Vezys V, et al.: Dynamic T cell migration program provides resident memory within intestinal epithelium. J Exp Med 2010, 207:553–564.CrossRefPubMedGoogle Scholar
  36. 36.
    Zufferey C, Erhart D, Saurer L, Mueller C: Production of interferon-gamma by activated T-cell receptor-alphabeta CD8alphabeta intestinal intraepithelial lymphocytes is required and sufficient for disruption of the intestinal barrier integrity. Immunology 2009, 128:351–359.CrossRefPubMedGoogle Scholar
  37. 37.
    Shibahara T, Miyazaki K, Sato D, et al.: Alteration of intestinal epithelial function by intraepithelial lymphocyte homing. J Gastroenterol 2005, 40:878–886.CrossRefPubMedGoogle Scholar
  38. 38.
    von Andrian UH, Engelhardt B: Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med 2003, 348:68–72.CrossRefGoogle Scholar
  39. 39.
    Briskin M, Winsor-Hines D, Shyjan A, et al.: Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 1997, 151:97–110.PubMedGoogle Scholar
  40. 40.
    Hamann A, Andrew DP, Jablonski-Westrich D, et al.: Role of a4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 1994, 152:3282–3293.PubMedGoogle Scholar
  41. 41.
    Lefrancois L, Parker CM, Olson S, et al.: The role of beta7 integrins in CD8 T cell trafficking during an antiviral immune response. J Exp Med 1999, 189:1631–1638.CrossRefPubMedGoogle Scholar
  42. 42.
    Sandborn WJ, Colombel JF, Enns R, et al.: Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005, 353:1912–1925.CrossRefPubMedGoogle Scholar
  43. 43.
    Feagan BG, Greenberg GR, Wild G, et al.: Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 2005, 352:2499–2507.CrossRefPubMedGoogle Scholar
  44. 44.
    Ghosh S, Goldin E, Gordon FH, et al.: Natalizumab for active Crohn’s disease. N Engl J Med 2003, 348:24–32.CrossRefPubMedGoogle Scholar
  45. 45.
    Bickston SJ, Muniyappa K: Natalizumab for the treatment of Crohn’s disease. Expert Rev Clin Immunol 2010, 6:513–519.CrossRefPubMedGoogle Scholar
  46. 46.
    Baumgart DC: Veto on vedolizumab (MLN0002) for Crohn’s disease. Inflamm Bowel Dis 2010, 16:537–538.PubMedGoogle Scholar
  47. 47.
    Kim SK, Schluns KS, Lefrançois L: Induction and visualization of mucosal memory CD8 T cells following systemic virus infection. J Immunol 1999, 163:4125–4132.PubMedGoogle Scholar
  48. 48.
    Schon MP, Arya A, Murphy EA, et al.: Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. J Immunol 1999, 162:6641–6699.PubMedGoogle Scholar
  49. 49.
    El-Asady R, Yuan R, Liu K, et al.: TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease. J Exp Med 2005, 201:1647–1657.CrossRefPubMedGoogle Scholar
  50. 50.
    Schlickum S, Sennefelder H, Friedrich M, et al.: Integrin alpha E(CD103)beta 7 influences cellular shape and motility in a ligand-dependent fashion. Blood 2008, 112:619–625.CrossRefPubMedGoogle Scholar
  51. 51.•
    Le FA, Jalil A, Vergnon I, et al.: Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J Exp Med 2007, 204:559–570. This paper was the first to demonstrate a costimulatory role for CD103 expression on CD8αβ + T cells. Using an E-cadherin–expressing tumor, the authors showed that CD103 mediates lytic granule polarization and tumor lysis.CrossRefGoogle Scholar
  52. 52.
    Blaser C, Kaufmann M, Pircher H: Virus-activated CD8 T cells and lymphokine-activated NK cells express the mast cell function-associated antigen, an inhibitory C-type lectin. J Immunol 1998, 161:6451–6454.PubMedGoogle Scholar
  53. 53.
    Ito M, Maruyama T, Saito N, et al.: Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J Exp Med 2006, 203:289–295.CrossRefPubMedGoogle Scholar
  54. 54.
    Obar JJ, Lefrancois L: Memory CD8+ T cell differentiation. Ann N Y Acad Sci 2010, 1183:251–266.CrossRefPubMedGoogle Scholar
  55. 55.
    Hand TW, Morre M, Kaech SM: Expression of IL-7 receptor alpha is necessary but not sufficient for the formation of memory CD8 T cells during viral infection. Proc Natl Acad Sci U S A 2007, 104:11730–11735.CrossRefPubMedGoogle Scholar
  56. 56.
    Joshi NS, Cui W, Chandele A, et al.: Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 2007, 27:281–295.CrossRefPubMedGoogle Scholar
  57. 57.
    Robbins SH, Terrizzi SC, Sydora BC, et al.: Differential regulation of killer cell lectin-like receptor G1 expression on T cells. J Immunol 2003, 170:5876–5885.PubMedGoogle Scholar
  58. 58.
    Sanjabi S, Mosaheb MM, Flavell RA: Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity 2009, 31:131–144.CrossRefPubMedGoogle Scholar
  59. 59.
    Wurbel MA, Malissen M, Guy-Grand D, et al.: Impaired accumulation of antigen-specific CD8 lymphocytes in chemokine CCL25-deficient intestinal epithelium and lamina propria. J Immunol 2007, 178:7598–7606.PubMedGoogle Scholar
  60. 60.
    Ericsson A, Svensson M, Arya A, Agace WW: CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes. Eur J Immunol 2004, 34:2720–2729.CrossRefPubMedGoogle Scholar
  61. 61.
    Walters M, Wang Y, Lai N, et al.: Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for the treatment of inflammatory bowel disease. J Pharmacol Exp Ther 2010 (Epub ahead of print).Google Scholar
  62. 62.
    Poussier P, Edouard P, Lee C, et al.: Thymus-independent development and negative selection of T cells expressing T cell receptor α/β in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes. J Exp Med 1992, 176:187–199.CrossRefPubMedGoogle Scholar
  63. 63.
    Suzuki S, Sugahara S, Shimizu T, et al.: Low level of mixing of partner cells seen in extrathymic T cells in the liver and intestine of parabiotic mice: its biological implication. Eur J Immunol 1998, 28:3719–3729.CrossRefPubMedGoogle Scholar
  64. 64.
    Stankovic S, Zhan Y, Harrison LC: Homeostatic proliferation of intestinal intraepithelial lymphocytes precedes their migration to extra-intestinal sites. Eur J Immunol 2007, 37:2226–2233.CrossRefPubMedGoogle Scholar
  65. 65.
    Wells JM, Loonen LM, Karczewski JM: The role of innate signaling in the homeostasis of tolerance and immunity in the intestine. Int J Med Microbiol 2010, 300:41–48.CrossRefPubMedGoogle Scholar
  66. 66.•
    Brandl K, Plitas G, Schnabl B, et al.: MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J Exp Med 2007, 204:1891–1900. This paper demonstrates that IEC-dependent MyD88 signals regulate innate intestinal immunity to an oral Listeria monocytogenes infection.CrossRefPubMedGoogle Scholar
  67. 67.
    Lebeis SL, Bommarius B, Parkos CA, et al.: TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J Immunol 2007, 179:566–577.PubMedGoogle Scholar
  68. 68.
    Schluns KS, Nowak EC, Cabrera-Hernandez A, et al.: Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor alpha expression. Proc Natl Acad Sci U S A 2004, 101:5616–5621.CrossRefPubMedGoogle Scholar
  69. 69.••
    Malamut G, El MR, Montcuquet N, et al.: IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 2010, 120:2131–2143. This paper (along with reference [70••]) identifies multiple novel therapeutic targets in the treatment of celiac disease. Specifically, the authors used freshly isolated human IELs and human IEL cell lines from CD patients to demonstrate the importance of IL-15 and its downstream signaling intermediaries to CD pathogenesis.CrossRefPubMedGoogle Scholar
  70. 70.••
    Yokoyama S, Watanabe N, Sato N, 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 U S A 2009, 106:15849–15854. This paper (along with reference [69••]) identifies multiple novel therapeutic targets in the treatment of celiac disease. Specifically, the authors demonstrate the blockade of IL-15 signals as potential targets to reduce intestinal damage in a murine model of CD.CrossRefPubMedGoogle Scholar
  71. 71.
    Taylor BC, Zaph C, Troy AE, et al.: TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J Exp Med 2009, 206:655–667.CrossRefPubMedGoogle Scholar
  72. 72.
    Rimoldi M, Chieppa M, Salucci V, et al.: Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol 2005, 6:507–514.CrossRefPubMedGoogle Scholar
  73. 73.
    Rochman Y, Leonard WJ: The role of thymic stromal lymphopoietin in CD8+ T cell homeostasis. J Immunol 2008, 181:7699–7705.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of ImmunologyUniversity of Connecticut Health CenterFarmingtonUSA

Personalised recommendations