Journal of Gastroenterology

, Volume 40, Issue 9, pp 878–886 | Cite as

Alteration of intestinal epithelial function by intraepithelial lymphocyte homing

  • Takeshi Shibahara
  • Kaori Miyazaki
  • Daisuke Sato
  • Hirohumi Matsui
  • Akinori Yanaka
  • Akira Nakahara
  • Naomi Tanaka



Intimate cross-talk may take place between intestinal epithelial cells and intraepithelial lymphocytes (IEL). The purpose of this study was to analyze the influence of lymphocyte migration into the epithelium on epithelial function, using an in vitro “IEL homing” model.


Molecular expression on epithelial cells was analyzed by flow cytometry. The barrier function of the epithelial monolayer was assessed by transepithelial electrical resistance. Cytokine production was measured by enzyme-linked immunosorbent assay (ELISA).


(1) IEL homing into the epithelia induced significant phenotypic changes in epithelial cells; upregulation of MHC class I, and II, intercellular adhesion molecule (ICAM)-1, and CD44. IEL-derived interferon-γ (IFN-γ) could partially account for this alteration, as a neutralizing antibody (Ab) against IFN-γ inhibited the upregulation of these molecules, except for CD44. (2) A marked fall in transepithelial electrical resistance was observed 4 h after IEL homing started, and Ab against IFN-γ slightly inhibited this fall in resistance. (3) The production of interleukin (IL)-8 and IFN-γ inducible protein-10 (IP-10), but not transforming growth factor (TGF)-β1 or tumor necrosis factor (TNF)-α, in the epithelial monolayer was markedly induced after IEL homing in a basolaterally polarized fashion. IEL-conditioned media also induced the production of these cytokines in epithelial cells, thus suggesting that IEL-derived soluble factor(s) induce epithelial chemokine production.


Under inflammatory conditions, IEL obviously interact with epithelial cells and upregulate adhesion molecules, alter barrier function, and enhance chemokine production. Because such alterations may increase epithelial permeability to luminal antigens or accelerate the migration of other inflammatory cells, our results suggest that IEL have a critical role in mucosal immunity.

Key words

intraepithelial lymphocytes epithelial function mucosal immunity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Brandtzaeg, P, Halstensen, TS, Kett, K, Krajci, P, Kvale, D, Rognum, TO,  et al. 1989Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytesGastroenterology97156284PubMedGoogle Scholar
  2. 2.
    Shanahan, F 1999Intestinal lymphoepithelial communicationAdv Exp Med Biol47319Google Scholar
  3. 3.
    Bland, PW 1998Mucosal T cell-epithelial cell interactionsChem Immunol714063PubMedGoogle Scholar
  4. 4.
    Shibahara, T, Wilcox, JN, Couse, T, Madara, JL 2001Characterization of epithelial chemoattractants for human intestinal intraepithelial lymphocytesGastroenterology1206070CrossRefPubMedGoogle Scholar
  5. 5.
    Reinecker, HC, MacDermott, RP, Mirau, S, Dignass, A, Podolsky, DK 1996Intestinal epithelial cells both express and respond to interleukin 15Gastroenterology111170613PubMedGoogle Scholar
  6. 6.
    Watanabe, M, Ueno, Y, Yajima, T, Iwao, Y, Tsuchiya, M, Ishikawa, H,  et al. 1995Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytesJ Clin Invest95294553PubMedGoogle Scholar
  7. 7.
    Wang, J, Whetsell, M, Klein, JR 1997Local hormone networks and intestinal T cell homeostasisScience27519379CrossRefPubMedGoogle Scholar
  8. 8.
    Parkos, CA, Colgan, SP, Diamond, MS, Nusrat, A, Liang, TW, Springer, TA,  et al. 1996Expression and polarization of intercellular adhesion molecule-1 on human intestinal epithelia: consequences for CD11b/CD18-mediated interactions with neutrophilsMol Med2489505PubMedGoogle Scholar
  9. 9.
    Colgan, SP, Morales, VM, Madara, JL, Polischuk, JE, Balk, SP, Blumberg, RS 1996IFN-gamma modulates CD1d surface expression on intestinal epitheliaAm J Physiol271C27683PubMedGoogle Scholar
  10. 10.
    Boismenu, R, Havran, WL 1994Modulation of epithelial cell growth by intraepithelial gamma delta T cellsScience26612535PubMedGoogle Scholar
  11. 11.
    Shaw, SK, Hermanowski-Vosatka, A, Shibahara, T, McCormick, BA, Parkos, CA, Carlson, SL,  et al. 1998Migration of intestinal intraepithelial lymphocytes into a polarized epithelial monolayerAm J Physiol275G58491PubMedGoogle Scholar
  12. 12.
    Shibahara, T, Si-Tahar, M, Shaw, SK, Madara, JL 2000Adhesion molecules expressed on homing lymphocytes in model intestinal epitheliaGastroenterology11828998PubMedGoogle Scholar
  13. 13.
    Cepek, KL, Parker, CM, Madara, JL, Brenner, MB 1993Integrin alpha E beta 7 mediates adhesion of T lymphocytes to epithelial cellsJ Immunol150345970PubMedGoogle Scholar
  14. 14.
    Kaiserlian, D, Rigal, D, Abello, J, Revillard, JP 1991Expression, function and regulation of the intercellular adhesion molecule-1 (ICAM-1) on human intestinal epithelial cell linesEur J Immunol21241521PubMedGoogle Scholar
  15. 15.
    Colgan, SP, Parkos, CA, Matthews, JB, D'Andrea, L, Awtrey, CS, Lichtman, AH,  et al. 1994Interferon-gamma induces a cell surface phenotype switch on T84 intestinal epithelial cellsAm J Physiol267C40210PubMedGoogle Scholar
  16. 16.
    Dharmsathaphorn, K, Madara, JL 1990Established intestinal cell lines as model systems for electrolyte transport studiesMethods Enzymol19235489PubMedGoogle Scholar
  17. 17.
    Madara, JL, Stafford, J 1989Interferon-gamma directly affects barrier function of cultured intestinal epithelial monolayersJ Clin Invest837247PubMedGoogle Scholar
  18. 18.
    Youakim, A, Ahdieh, M 1999Interferon-gamma decreases barrier function in T84 cells by reducing ZO-1 levels and disrupting apical actinAm J Physiol276G127988PubMedGoogle Scholar
  19. 19.
    Schmitz, H, Fromm, M, Bentzel, CJ, Scholz, P, Detjen, K, Mankertz, J,  et al. 1999Tumor necrosis factor-alpha (TNFalpha) regulates the epithelial barrier in the human intestinal cell line HT-29/B6J Cell Sci11213746PubMedGoogle Scholar
  20. 20.
    Gitter, AH, Bendfeldt, K, Schmitz, H, Schulzke, JD, Bentzel, CJ, Fromm, M 2000Epithelial barrier defects in HT-29/B6 colonic cell monolayers induced by tumor necrosis factor-alphaAnn N Y Acad Sci915193203PubMedGoogle Scholar
  21. 21.
    Mayer, L, Eisenhardt, D, Salomon, P, Bauer, W, Plous, R, Piccinini, L 1991Expression of class II molecules on intestinal epithelial cells in humans. Differences between normal and inflammatory bowel diseaseGastroenterology100312PubMedGoogle Scholar
  22. 22.
    Geppert, TD, Lipsky, PE 1985Antigen presentation by interferon-gamma-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expressionJ Immunol135375062PubMedGoogle Scholar
  23. 23.
    Mayer, L, Shlien, R 1987Evidence for function of Ia molecules on gut epithelial cells in manJ Exp Med166147183CrossRefPubMedGoogle Scholar
  24. 24.
    Hershberg, RM, Framson, PE, Cho, DH, Lee, LY, Kovats, S, Beitz, J,  et al. 1997Intestinal epithelial cells use two distinct pathways for HLA class II antigen processingJ Clin Invest10020415PubMedGoogle Scholar
  25. 25.
    Hershberg, RM, Cho, DH, Youakim, A, Bradley, MB, Lee, JS, Framson, PE,  et al. 1998Highly polarized HLA class II antigen processing and presentation by human intestinal epithelial cellsJ Clin Invest102792803PubMedGoogle Scholar
  26. 26.
    Paolieri, F, Battifora, M, Riccio, AM, Pesce, G, Canonica, GW, Bagnasco, M 1997Intercellular adhesion molecule-1 on cultured human epithelial cell lines: influence of proinflammatory cytokinesAllergy5252131PubMedGoogle Scholar
  27. 27.
    Roberts, AI, O'Connell, SM, Ebert, EC 1993Intestinal intraepithelial lymphocytes bind to colon cancer cells by HML-1 and CD11aCancer Res53160811PubMedGoogle Scholar
  28. 28.
    Ni, J, Hollander, D, Sydora, B, Panwala, C 1995Adhesion molecule expression and adhesion properties of murine intestinal intraepithelial lymphocyte hybridomasCell Immunol16415660CrossRefPubMedGoogle Scholar
  29. 29.
    Goodison, S, Urquidi, V, Tarin, D 1999CD44 cell adhesion moleculesMol Pathol5218996PubMedGoogle Scholar
  30. 30.
    McCormick, BA, Hofman, PM, Kim, J, Carnes, DK, Miller, SI, Madara, JL 1995Surface attachment of Salmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophilsJ Cell Biol1311599608CrossRefPubMedGoogle Scholar
  31. 31.
    Gewirtz, AT, Siber, AM, Madara, JL, McCormick, BA 1999Orchestration of neutrophil movement by intestinal epithelial cells in response to Salmonella typhimurium can be uncoupled from bacterial internalizationInfect Immun6760817PubMedGoogle Scholar
  32. 32.
    Jung, HC, Eckmann, L, Yang, SK, Panja, A, Fierer, J, Morzycka-Wroblewska, E,  et al. 1995A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasionJ Clin Invest955565PubMedGoogle Scholar
  33. 33.
    Eckmann, L, Kagnoff, MF, Falco, MT 1994Colonic epithelial cell lines as a source of interleukin-8: stimulation by inflammatory cytokines and bacterial lipopolysaccharideImmunology818591PubMedGoogle Scholar
  34. 34.
    Ebert, EC 1995Human intestinal intraepithelial lymphocytes have potent chemotactic activityGastroenterology10911549CrossRefPubMedGoogle Scholar
  35. 35.
    Roberts, AI, Bilenker, M, Ebert, EC 1997Intestinal intraepithelial lymphocytes have a promiscuous interleukin-8 receptorGut403338PubMedGoogle Scholar
  36. 36.
    Farber, JM 1997Mig and IP-10: CXC chemokines that target lymphocytesJ Leukoc Biol6124657PubMedGoogle Scholar
  37. 37.
    Taub, DD, Lloyd, AR, Conlon, K, Wang, JM, Ortaldo, JR, Harada, A,  et al. 1993Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cellsJ Exp Med177180914CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2005

Authors and Affiliations

  • Takeshi Shibahara
    • 1
  • Kaori Miyazaki
    • 1
  • Daisuke Sato
    • 1
  • Hirohumi Matsui
    • 1
  • Akinori Yanaka
    • 1
  • Akira Nakahara
    • 1
  • Naomi Tanaka
    • 1
  1. 1.Department of Gastroenterology, Institute of Clinical MedicineUniversity of TsukubaTsukubaJapan

Personalised recommendations