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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Apr 16;93(8):3613–3618. doi: 10.1073/pnas.93.8.3613

Interleukin 2 (IL-2) and interleukin 7 (IL-7) reciprocally induce IL-7 and IL-2 receptors on gamma delta T-cell receptor-positive intraepithelial lymphocytes.

K Fujihashi 1, S Kawabata 1, T Hiroi 1, M Yamamoto 1, J R McGhee 1, S Nishikawa 1, H Kiyono 1
PMCID: PMC39659  PMID: 8622984

Abstract

In this study, we describe the interaction between cytokine and cytokine receptor (R) for the activation and proliferation of gamma delta T-cell receptor-positive T cells (gamma delta T cells). gamma delta T cells isolated from murine intestinal intraepithelial lymphocytes (IELs) were separated into gamma delta (Dim) and gamma delta (Bright) fractions according to the intensity of gamma delta T-cell receptor expression. The gamma delta T cells express low levels of IL-2R and IL-7R as shown by flow cytometry and reverse transcriptase-PCR analysis, whereas gamma delta (Bright) T cells did not express either receptor. Our study also revealed that recombinant marine (rm)IL-2 and rmIL-7 reciprocally induced high expressions of IL-7R and IL-2R, respectively, on gamma delta (Dim) T cells but not on gamma delta (Bright) cells. Thus, treatment of gamma delta (Dim) T cells with rmIL-2 and rmIL-7 resulted in high proliferative responses, whereas gamma delta (Bright) T cells did not respond to these two cytokines. The sources of these two cytokines for gamma delta T cells were neighboring epithelial cells (IL-7) and alpha beta T cells (IL-2 and IL-7). Cytokine signaling by IL-2 and IL-7 from alpha beta T cells and epithelial cells was necessary for the expression of IL-7R and IL-2R, respectively, on a subset of gamma delta T cells (e.g., gamma delta (Dim) T cells) in mucosa-associated tissue for subsequent activation and cell division.

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  1. Armitage R. J., Namen A. E., Sassenfeld H. M., Grabstein K. H. Regulation of human T cell proliferation by IL-7. J Immunol. 1990 Feb 1;144(3):938–941. [PubMed] [Google Scholar]
  2. Bonneville M., Janeway C. A., Jr, Ito K., Haser W., Ishida I., Nakanishi N., Tonegawa S. Intestinal intraepithelial lymphocytes are a distinct set of gamma delta T cells. Nature. 1988 Dec 1;336(6198):479–481. doi: 10.1038/336479a0. [DOI] [PubMed] [Google Scholar]
  3. Chazen G. D., Pereira G. M., LeGros G., Gillis S., Shevach E. M. Interleukin 7 is a T-cell growth factor. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5923–5927. doi: 10.1073/pnas.86.15.5923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Conlon P. J., Morrissey P. J., Nordan R. P., Grabstein K. H., Prickett K. S., Reed S. G., Goodwin R., Cosman D., Namen A. E. Murine thymocytes proliferate in direct response to interleukin-7. Blood. 1989 Sep;74(4):1368–1373. [PubMed] [Google Scholar]
  5. Fabbi M., Groh V., Strominger J. L. IL-7 induces proliferation of CD3-/low CD4- CD8- human thymocyte precursors by an IL-2 independent pathway. Int Immunol. 1992 Jan;4(1):1–5. doi: 10.1093/intimm/4.1.1. [DOI] [PubMed] [Google Scholar]
  6. Ferguson A., Parrott D. M. The effect of antigen deprivation on thymus-dependent and thymus-independent lymphocytes in the small intestine of the mouse. Clin Exp Immunol. 1972 Dec;12(4):477–488. [PMC free article] [PubMed] [Google Scholar]
  7. Fujihashi K., Taguchi T., Aicher W. K., McGhee J. R., Bluestone J. A., Eldridge J. H., Kiyono H. Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR+) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help. J Exp Med. 1992 Mar 1;175(3):695–707. doi: 10.1084/jem.175.3.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fujihashi K., Yamamoto M., McGhee J. R., Beagley K. W., Kiyono H. Function of alpha beta TCR+ intestinal intraepithelial lymphocytes: Th1- and Th2-type cytokine production by CD4+CD8- and CD4+CD8+ T cells for helper activity. Int Immunol. 1993 Nov;5(11):1473–1481. doi: 10.1093/intimm/5.11.1473. [DOI] [PubMed] [Google Scholar]
  9. Garman R. D., Jacobs K. A., Clark S. C., Raulet D. H. B-cell-stimulatory factor 2 (beta 2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7629–7633. doi: 10.1073/pnas.84.21.7629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gilliland G., Perrin S., Blanchard K., Bunn H. F. Analysis of cytokine mRNA and DNA: detection and quantitation by competitive polymerase chain reaction. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2725–2729. doi: 10.1073/pnas.87.7.2725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Goodman T., Lefrançois L. Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature. 1988 Jun 30;333(6176):855–858. doi: 10.1038/333855a0. [DOI] [PubMed] [Google Scholar]
  12. Grabstein K. H., Namen A. E., Shanebeck K., Voice R. F., Reed S. G., Widmer M. B. Regulation of T cell proliferation by IL-7. J Immunol. 1990 Apr 15;144(8):3015–3020. [PubMed] [Google Scholar]
  13. Grabstein K. H., Park L. S., Morrissey P. J., Sassenfeld H., Price V., Urdal D. L., Widmer M. B. Regulation of murine T cell proliferation by B cell stimulatory factor-1. J Immunol. 1987 Aug 15;139(4):1148–1153. [PubMed] [Google Scholar]
  14. Henney C. S. Interleukin 7: effects on early events in lymphopoiesis. Immunol Today. 1989 May;10(5):170–173. doi: 10.1016/0167-5699(89)90175-8. [DOI] [PubMed] [Google Scholar]
  15. Hiroi T., Fujihashi K., McGhee J. R., Kiyono H. Polarized Th2 cytokine expression by both mucosal gamma delta and alpha beta T cells. Eur J Immunol. 1995 Oct;25(10):2743–2751. doi: 10.1002/eji.1830251005. [DOI] [PubMed] [Google Scholar]
  16. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  17. Komano H., Fujiura Y., Kawaguchi M., Matsumoto S., Hashimoto Y., Obana S., Mombaerts P., Tonegawa S., Yamamoto H., Itohara S. Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):6147–6151. doi: 10.1073/pnas.92.13.6147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kondo M., Takeshita T., Higuchi M., Nakamura M., Sudo T., Nishikawa S., Sugamura K. Functional participation of the IL-2 receptor gamma chain in IL-7 receptor complexes. Science. 1994 Mar 11;263(5152):1453–1454. doi: 10.1126/science.8128231. [DOI] [PubMed] [Google Scholar]
  19. Leclercq G., De Smedt M., Plum J. Presence of CD8 alpha-CD8 beta-positive TcR gamma/delta thymocytes in the fetal murine thymus and their in vitro expansion with interleukin-7. Eur J Immunol. 1992 Sep;22(9):2189–2193. doi: 10.1002/eji.1830220902. [DOI] [PubMed] [Google Scholar]
  20. Lowenthal J. W., Corthésy P., Tougne C., Lees R., MacDonald H. R., Nabholz M. High and low affinity IL 2 receptors: analysis by IL 2 dissociation rate and reactivity with monoclonal anti-receptor antibody PC61. J Immunol. 1985 Dec;135(6):3988–3994. [PubMed] [Google Scholar]
  21. Mizel S. B. Interleukin 1 and T cell activation. Immunol Rev. 1982;63:51–72. doi: 10.1111/j.1600-065x.1982.tb00411.x. [DOI] [PubMed] [Google Scholar]
  22. Morrissey P. J., Goodwin R. G., Nordan R. P., Anderson D., Grabstein K. H., Cosman D., Sims J., Lupton S., Acres B., Reed S. G. Recombinant interleukin 7, pre-B cell growth factor, has costimulatory activity on purified mature T cells. J Exp Med. 1989 Mar 1;169(3):707–716. doi: 10.1084/jem.169.3.707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mosley R. L., Whetsell M., Klein J. R. Proliferative properties of murine intestinal intraepithelial lymphocytes (IEL): IEL expressing TCR alpha beta or TCR tau delta are largely unresponsive to proliferative signals mediated via conventional stimulation of the CD3-TCR complex. Int Immunol. 1991 Jun;3(6):563–569. doi: 10.1093/intimm/3.6.563. [DOI] [PubMed] [Google Scholar]
  24. Namen A. E., Lupton S., Hjerrild K., Wignall J., Mochizuki D. Y., Schmierer A., Mosley B., March C. J., Urdal D., Gillis S. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature. 1988 Jun 9;333(6173):571–573. doi: 10.1038/333571a0. [DOI] [PubMed] [Google Scholar]
  25. Namen A. E., Schmierer A. E., March C. J., Overell R. W., Park L. S., Urdal D. L., Mochizuki D. Y. B cell precursor growth-promoting activity. Purification and characterization of a growth factor active on lymphocyte precursors. J Exp Med. 1988 Mar 1;167(3):988–1002. doi: 10.1084/jem.167.3.988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Noguchi M., Nakamura Y., Russell S. M., Ziegler S. F., Tsang M., Cao X., Leonard W. J. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science. 1993 Dec 17;262(5141):1877–1880. doi: 10.1126/science.8266077. [DOI] [PubMed] [Google Scholar]
  27. Okazaki H., Ito M., Sudo T., Hattori M., Kano S., Katsura Y., Minato N. IL-7 promotes thymocyte proliferation and maintains immunocompetent thymocytes bearing alpha beta or gamma delta T-cell receptors in vitro: synergism with IL-2. J Immunol. 1989 Nov 1;143(9):2917–2922. [PubMed] [Google Scholar]
  28. Siebert P. D., Larrick J. W. Competitive PCR. Nature. 1992 Oct 8;359(6395):557–558. doi: 10.1038/359557a0. [DOI] [PubMed] [Google Scholar]
  29. Skeen M. J., Ziegler H. K. Intercellular interactions and cytokine responsiveness of peritoneal alpha/beta and gamma/delta T cells from Listeria-infected mice: synergistic effects of interleukin 1 and 7 on gamma/delta T cells. J Exp Med. 1993 Sep 1;178(3):985–996. doi: 10.1084/jem.178.3.985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stötter H., Custer M. C., Bolton E. S., Guedez L., Lotze M. T. IL-7 induces human lymphokine-activated killer cell activity and is regulated by IL-4. J Immunol. 1991 Jan 1;146(1):150–155. [PubMed] [Google Scholar]
  31. Sudo T., Nishikawa S., Ohno N., Akiyama N., Tamakoshi M., Yoshida H., Nishikawa S. Expression and function of the interleukin 7 receptor in murine lymphocytes. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9125–9129. doi: 10.1073/pnas.90.19.9125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Taguchi T., Aicher W. K., Fujihashi K., Yamamoto M., McGhee J. R., Bluestone J. A., Kiyono H. Novel function for intestinal intraepithelial lymphocytes. Murine CD3+, gamma/delta TCR+ T cells produce IFN-gamma and IL-5. J Immunol. 1991 Dec 1;147(11):3736–3744. [PubMed] [Google Scholar]
  33. Tauchi Y., Matsuzaki G., Takimoto H., Yoshikai Y., Nomoto K. A new subpopulation of intestinal intraepithelial lymphocytes expressing high level of T cell receptor gamma delta. Eur J Immunol. 1992 Sep;22(9):2465–2468. doi: 10.1002/eji.1830220943. [DOI] [PubMed] [Google Scholar]
  34. Watanabe M., Ueno Y., Yajima T., Iwao Y., Tsuchiya M., Ishikawa H., Aiso S., Hibi T., Ishii H. Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J Clin Invest. 1995 Jun;95(6):2945–2953. doi: 10.1172/JCI118002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Watanabe Y., Sudo T., Minato N., Ohnishi A., Katsura Y. Interleukin 7 preferentially supports the growth of gamma delta T cell receptor-bearing T cells from fetal thymocytes in vitro. Int Immunol. 1991 Nov;3(11):1067–1075. doi: 10.1093/intimm/3.11.1067. [DOI] [PubMed] [Google Scholar]
  36. Watson J. D., Morrissey P. J., Namen A. E., Conlon P. J., Widmer M. B. Effect of IL-7 on the growth of fetal thymocytes in culture. J Immunol. 1989 Aug 15;143(4):1215–1222. [PubMed] [Google Scholar]
  37. Watson J., Mochizuki D. Interleukin 2: a class of T cell growth factors. Immunol Rev. 1980;51:257–278. doi: 10.1111/j.1600-065x.1980.tb00324.x. [DOI] [PubMed] [Google Scholar]
  38. Weiser M. M. Intestinal epithelial cell surface membrane glycoprotein synthesis. I. An indicator of cellular differentiation. J Biol Chem. 1973 Apr 10;248(7):2536–2541. [PubMed] [Google Scholar]
  39. Yamamoto M., Fujihashi K., Beagley K. W., McGhee J. R., Kiyono H. Cytokine synthesis by intestinal intraepithelial lymphocytes. Both gamma/delta T cell receptor-positive and alpha/beta T cell receptor-positive T cells in the G1 phase of cell cycle produce IFN-gamma and IL-5. J Immunol. 1993 Jan 1;150(1):106–114. [PubMed] [Google Scholar]

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