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. 1990 Aug 1;172(2):439–446. doi: 10.1084/jem.172.2.439

A role for interleukin 4 in the differentiation of mature T cell receptor gamma/delta + cells from human intrathymic T cell precursors

PMCID: PMC2188331  PMID: 2373988

Abstract

We have analyzed the effect of human recombinant interleukin 4 (rIL-4) on the growth and differentiation of human intrathymic pre-T cells (CD7+2+1-3-4-8-). We describe that this population of T cell precursors proliferates in response to rIL-4 (in the absence of mitogens or other stimulatory signals) in a dose-dependent way. The IL-4-induced proliferation is independent of the IL-2 pathway, as it cannot be inhibited with an anti-IL-2 receptor alpha chain antibody. In our culture conditions, rIL-4 also promotes the differentiation of pre-T cells into phenotypically mature T cells. Although both CD3/T cell receptor (TCR)-alpha/beta + and CD3-gamma/delta + T cells were obtained, the preferential differentiation into TCR-gamma/delta + cells was a consistent finding. These results suggest that, in addition to IL- 2, IL-4 plays a critical role in promoting growth and differentiation of intrathymic T cell precursors at early stages of T cell development.

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Selected References

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  1. Band H., Hochstenbach F., McLean J., Hata S., Krangel M. S., Brenner M. B. Immunochemical proof that a novel rearranging gene encodes the T cell receptor delta subunit. Science. 1987 Oct 30;238(4827):682–684. doi: 10.1126/science.3672118. [DOI] [PubMed] [Google Scholar]
  2. Barnstable C. J., Bodmer W. F., Brown G., Galfre G., Milstein C., Williams A. F., Ziegler A. Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis. Cell. 1978 May;14(1):9–20. doi: 10.1016/0092-8674(78)90296-9. [DOI] [PubMed] [Google Scholar]
  3. Brown M., Hu-Li J., Paul W. E. IL-4/B cell stimulatory factor 1 stimulates T cell growth by an IL-2-independent mechanism. J Immunol. 1988 Jul 15;141(2):504–511. [PubMed] [Google Scholar]
  4. Carding S. R., Jenkinson E. J., Kingston R., Hayday A. C., Bottomly K., Owen J. J. Developmental control of lymphokine gene expression in fetal thymocytes during T-cell ontogeny. Proc Natl Acad Sci U S A. 1989 May;86(9):3342–3345. doi: 10.1073/pnas.86.9.3342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carrera A. C., Sanchez-Madrid F., Lopez-Botet M., Bernabeu C., De Landazuri M. O. Involvement of the CD4 molecule in a post-activation event on T cell proliferation. Eur J Immunol. 1987 Feb;17(2):179–186. doi: 10.1002/eji.1830170205. [DOI] [PubMed] [Google Scholar]
  6. De la Hera A., Toribio M. L., Marcos M. A., Marquez C., Martinez C. Interleukin 2 pathway is autonomously activated in human T11+3-4-6-8- thymocytes. Eur J Immunol. 1987 May;17(5):683–687. doi: 10.1002/eji.1830170516. [DOI] [PubMed] [Google Scholar]
  7. Eisenbarth G. S., Haynes B. F., Schroer J. A., Fauci A. S. Production of monoclonal antibodies reacting with peripheral blood mononuclear cell surface differentiation antigens. J Immunol. 1980 Mar;124(3):1237–1244. [PubMed] [Google Scholar]
  8. Fernandez-Botran R., Krammer P. H., Diamantstein T., Uhr J. W., Vitetta E. S. B cell-stimulatory factor 1 (BSF-1) promotes growth of helper T cell lines. J Exp Med. 1986 Aug 1;164(2):580–593. doi: 10.1084/jem.164.2.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fernandez-Botran R., Sanders V. M., Mosmann T. R., Vitetta E. S. Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells. J Exp Med. 1988 Aug 1;168(2):543–558. doi: 10.1084/jem.168.2.543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fernandez-Botran R., Sanders V. M., Oliver K. G., Chen Y. W., Krammer P. H., Uhr J. W., Vitetta E. S. Interleukin 4 mediates autocrine growth of helper T cells after antigenic stimulation. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9689–9693. doi: 10.1073/pnas.83.24.9689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fernandez-Botran R., Sanders V. M., Vitetta E. S. Interactions between receptors for interleukin 2 and interleukin 4 on lines of helper T cells (HT-2) and B lymphoma cells (BCL1). J Exp Med. 1989 Feb 1;169(2):379–391. doi: 10.1084/jem.169.2.379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Foxwell B. M., Woerly G., Ryffel B. Identification of interleukin 4 receptor-associated proteins and expression of both high- and low-affinity binding on human lymphoid cells. Eur J Immunol. 1989 Sep;19(9):1637–1641. doi: 10.1002/eji.1830190918. [DOI] [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. Grabstein K., Eisenman J., Mochizuki D., Shanebeck K., Conlon P., Hopp T., March C., Gillis S. Purification to homogeneity of B cell stimulating factor. A molecule that stimulates proliferation of multiple lymphokine-dependent cell lines. J Exp Med. 1986 Jun 1;163(6):1405–1414. doi: 10.1084/jem.163.6.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Haynes B. F., Denning S. M., Singer K. H., Kurtzberg J. Ontogeny of T-cell precursors: a model for the initial stages of human T-cell development. Immunol Today. 1989 Mar;10(3):87–91. doi: 10.1016/0167-5699(89)90232-6. [DOI] [PubMed] [Google Scholar]
  16. Howard M., Farrar J., Hilfiker M., Johnson B., Takatsu K., Hamaoka T., Paul W. E. Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med. 1982 Mar 1;155(3):914–923. doi: 10.1084/jem.155.3.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hu-Li J., Shevach E. M., Mizuguchi J., Ohara J., Mosmann T., Paul W. E. B cell stimulatory factor 1 (interleukin 4) is a potent costimulant for normal resting T lymphocytes. J Exp Med. 1987 Jan 1;165(1):157–172. doi: 10.1084/jem.165.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lowenthal J. W., Ransom J., Howard M., Zlotnik A. Up-regulation of interleukin 4 receptor expression on immature (Lyt-2-/L3T4-) thymocytes. J Immunol. 1988 Jan 15;140(2):474–478. [PubMed] [Google Scholar]
  19. Malissen B., Rebai N., Liabeuf A., Mawas C. Human cytotoxic T cell structures associated with expression of cytolysis. I. Analysis at the clonal cell level of the cytolysis-inhibiting effect of 7 monoclonal antibodies. Eur J Immunol. 1982 Sep;12(9):739–747. doi: 10.1002/eji.1830120908. [DOI] [PubMed] [Google Scholar]
  20. McMichael A. J., Pilch J. R., Galfré G., Mason D. Y., Fabre J. W., Milstein C. A human thymocyte antigen defined by a hybrid myeloma monoclonal antibody. Eur J Immunol. 1979 Mar;9(3):205–210. doi: 10.1002/eji.1830090307. [DOI] [PubMed] [Google Scholar]
  21. Miethke T., Schmidberger R., Heeg K., Gillis S., Wagner H. Interleukin 4 (BSF-1) induces growth in resting murine CD8 T cells triggered via cross-linking of T3 cell surface structures. Eur J Immunol. 1988 May;18(5):767–772. doi: 10.1002/eji.1830180517. [DOI] [PubMed] [Google Scholar]
  22. Mosmann T. R., Bond M. W., Coffman R. L., Ohara J., Paul W. E. T-cell and mast cell lines respond to B-cell stimulatory factor 1. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5654–5658. doi: 10.1073/pnas.83.15.5654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nakamura Y., Inamoto T., Sugie K., Masutani H., Shindo T., Tagaya Y., Yamauchi A., Ozawa K., Yodoi J. Mitogenicity and down-regulation of high-affinity interleukin 2 receptor by YTA-1 and YTA-2, monoclonal antibodies that recognize 75-kDa molecules on human large granular lymphocytes. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1318–1322. doi: 10.1073/pnas.86.4.1318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Noma Y., Sideras P., Naito T., Bergstedt-Lindquist S., Azuma C., Severinson E., Tanabe T., Kinashi T., Matsuda F., Yaoita Y. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature. 1986 Feb 20;319(6055):640–646. doi: 10.1038/319640a0. [DOI] [PubMed] [Google Scholar]
  25. Ohara J., Paul W. E. Receptors for B-cell stimulatory factor-1 expressed on cells of haematopoietic lineage. Nature. 1987 Feb 5;325(6104):537–540. doi: 10.1038/325537a0. [DOI] [PubMed] [Google Scholar]
  26. Paliard X., Malefijt R. W., de Vries J. E., Spits H. Interleukin-4 mediates CD8 induction on human CD4+ T-cell clones. Nature. 1988 Oct 13;335(6191):642–644. doi: 10.1038/335642a0. [DOI] [PubMed] [Google Scholar]
  27. Pelkonen J., Sideras P., Rammensee H. G., Karjalainen K., Palacios R. Thymocyte clones from 14-day mouse embryos. I. State of T cell receptor genes, surface markers, and growth requirements. J Exp Med. 1987 Nov 1;166(5):1245–1258. doi: 10.1084/jem.166.5.1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sideras P., Funa K., Zalcberg-Quintana I., Xanthopoulos K. G., Kisielow P., Palacios R. Analysis by in situ hybridization of cells expressing mRNA for interleukin 4 in the developing thymus and in peripheral lymphocytes from mice. Proc Natl Acad Sci U S A. 1988 Jan;85(1):218–221. doi: 10.1073/pnas.85.1.218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Spits H., Yssel H., Leeuwenberg J., De Vries J. E. Antigen-specific cytotoxic T cell and antigen-specific proliferating T cell clones can be induced to cytolytic activity by monoclonal antibodies against T3. Eur J Immunol. 1985 Jan;15(1):88–91. doi: 10.1002/eji.1830150117. [DOI] [PubMed] [Google Scholar]
  30. Spits H., Yssel H., Takebe Y., Arai N., Yokota T., Lee F., Arai K., Banchereau J., de Vries J. E. Recombinant interleukin 4 promotes the growth of human T cells. J Immunol. 1987 Aug 15;139(4):1142–1147. [PubMed] [Google Scholar]
  31. Tentori L., Pardoll D. M., Zuñiga J. C., Hu-Li J., Paul W. E., Bluestone J. A., Kruisbeek A. M. Proliferation and production of IL-2 and B cell stimulatory factor 1/IL-4 in early fetal thymocytes by activation through Thy-1 and CD3. J Immunol. 1988 Feb 15;140(4):1089–1094. [PubMed] [Google Scholar]
  32. Toribio M. L., Martinez C., Marcos M. A., Marquez C., Cabrero E., de la Hera A. A role for T3+4-6-8- transitional thymocytes in the differentiation of mature and functional T cells from human prothymocytes. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6985–6988. doi: 10.1073/pnas.83.18.6985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Toribio M. L., de la Hera A., Borst J., Marcos M. A., Márquez C., Alonso J. M., Bárcena A., Martínez C. Involvement of the interleukin 2 pathway in the rearrangement and expression of both alpha/beta and gamma/delta T cell receptor genes in human T cell precursors. J Exp Med. 1988 Dec 1;168(6):2231–2249. doi: 10.1084/jem.168.6.2231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Widmer M. B., Acres R. B., Sassenfeld H. M., Grabstein K. H. Regulation of cytolytic cell populations from human peripheral blood by B cell stimulatory factor 1 (interleukin 4). J Exp Med. 1987 Nov 1;166(5):1447–1455. doi: 10.1084/jem.166.5.1447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zlotnik A., Ransom J., Frank G., Fischer M., Howard M. Interleukin 4 is a growth factor for activated thymocytes: possible role in T-cell ontogeny. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3856–3860. doi: 10.1073/pnas.84.11.3856. [DOI] [PMC free article] [PubMed] [Google Scholar]

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