Skip to main content
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
. 1991 Jul 15;88(14):6323–6327. doi: 10.1073/pnas.88.14.6323

Interleukin 7 receptor engagement stimulates tyrosine phosphorylation, inositol phospholipid turnover, proliferation, and selective differentiation to the CD4 lineage by human fetal thymocytes.

F M Uckun 1, L Tuel-Ahlgren 1, V Obuz 1, R Smith 1, I Dibirdik 1, M Hanson 1, M C Langlie 1, J A Ledbetter 1
PMCID: PMC52075  PMID: 2068112

Abstract

The purposes of this study were to elucidate the effects of recombinant human interleukin 7 (rhIL-7) on proliferation as well as differentiation of human fetal thymocytes and to analyze the biochemical nature of the IL-7 receptor-linked transmembrane signal. In the absence of costimulants, rhIL-7 stimulated the in vitro proliferation and colony formation of CD4+CD8+ double-positive immature fetal thymocytes. Furthermore, rhIL-7 promoted partial differentiation of immature thymocytes with a selective advantage for the development of CD4+CD8- single-positive thymocytes. Our observations suggest that IL-7 likely has an important regulatory role during the earliest stages of human T-cell ontogeny. Stimulation of fetal thymocytes with rhIL-7 resulted in enhanced tyrosine phosphorylation of three distinct phosphoproteins with molecular masses of 72, 98, 123, and 190 kDa and induced a rapid and biphasic increase in the production of inositol 1,4,5-trisphosphate, which was inhibitable by the tyrosine protein kinase inhibitor genistein. Thus, the transmembrane signal triggered by engagement of the IL-7 receptor is intimately linked to a functional tyrosine protein kinase pathway and stimulates the inositol phospholipid turnover and proliferation, as well as selective differentiation to the CD4 lineage, by human fetal thymocytes.

Full text

PDF
6325

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  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. 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]
  3. 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]
  4. Goodwin R. G., Lupton S., Schmierer A., Hjerrild K. J., Jerzy R., Clevenger W., Gillis S., Cosman D., Namen A. E. Human interleukin 7: molecular cloning and growth factor activity on human and murine B-lineage cells. Proc Natl Acad Sci U S A. 1989 Jan;86(1):302–306. doi: 10.1073/pnas.86.1.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Groh V., Fabbi M., Strominger J. L. Maturation or differentiation of human thymocyte precursors in vitro? Proc Natl Acad Sci U S A. 1990 Aug;87(15):5973–5977. doi: 10.1073/pnas.87.15.5973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Ledbetter J. A., Schieven G. L., Kuebelbeck V. M., Uckun F. M. Accessory receptors regulate coupling of the T-cell receptor complex to tyrosine kinase activation and mobilization of cytoplasmic calcium in T-lineage acute lymphoblastic leukemia. Blood. 1991 Mar 15;77(6):1271–1282. [PubMed] [Google Scholar]
  9. McConkey D. J., Hartzell P., Nicotera P., Orrenius S. Calcium-activated DNA fragmentation kills immature thymocytes. FASEB J. 1989 May;3(7):1843–1849. doi: 10.1096/fasebj.3.7.2497041. [DOI] [PubMed] [Google Scholar]
  10. Meisenhelder J., Suh P. G., Rhee S. G., Hunter T. Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro. Cell. 1989 Jun 30;57(7):1109–1122. doi: 10.1016/0092-8674(89)90048-2. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Mustelin T., Coggeshall K. M., Isakov N., Altman A. T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation. Science. 1990 Mar 30;247(4950):1584–1587. doi: 10.1126/science.2138816. [DOI] [PubMed] [Google Scholar]
  13. Nakayama T., Singer A., Hsi E. D., Samelson L. E. Intrathymic signalling in immature CD4+CD8+ thymocytes results in tyrosine phosphorylation of the T-cell receptor zeta chain. Nature. 1989 Oct 19;341(6243):651–654. doi: 10.1038/341651a0. [DOI] [PubMed] [Google Scholar]
  14. Nishibe S., Wahl M. I., Rhee S. G., Carpenter G. Tyrosine phosphorylation of phospholipase C-II in vitro by the epidermal growth factor receptor. J Biol Chem. 1989 Jun 25;264(18):10335–10338. [PubMed] [Google Scholar]
  15. 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]
  16. Preffer F. I., Kim C. W., Fischer K. H., Sabga E. M., Kradin R. L., Colvin R. B. Identification of pre-T cells in human peripheral blood. Extrathymic differentiation of CD7+CD3- cells into CD3+ gamma/delta+ or alpha/beta+ T cells. J Exp Med. 1989 Jul 1;170(1):177–190. doi: 10.1084/jem.170.1.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Smith C. A., Williams G. T., Kingston R., Jenkinson E. J., Owen J. J. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. doi: 10.1038/337181a0. [DOI] [PubMed] [Google Scholar]
  18. Uckun F. M., Dibirdik I., Smith R., Tuel-Ahlgren L., Chandan-Langlie M., Schieven G. L., Waddick K. G., Hanson M., Ledbetter J. A. Interleukin 7 receptor ligation stimulates tyrosine phosphorylation, inositol phospholipid turnover, and clonal proliferation of human B-cell precursors. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3589–3593. doi: 10.1073/pnas.88.9.3589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Uckun F. M., Gajl-Peczalska K., Meyers D. E., Ramsay N. C., Kersey J. H., Colvin M., Vallera D. A. Marrow purging in autologous bone marrow transplantation for T-lineage acute lymphoblastic leukemia: efficacy of ex vivo treatment with immunotoxins and 4-hydroperoxycyclophosphamide against fresh leukemic marrow progenitor cells. Blood. 1987 Jan;69(1):361–366. [PubMed] [Google Scholar]
  20. Uckun F. M., Ledbetter J. A. Immunobiologic differences between normal and leukemic human B-cell precursors. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8603–8607. doi: 10.1073/pnas.85.22.8603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Uckun F. M., Muraguchi A., Ledbetter J. A., Kishimoto T., O'Brien R. T., Roloff J. S., Gajl-Peczalska K., Provisor A., Koller B. Biphenotypic leukemic lymphocyte precursors in CD2+CD19+ acute lymphoblastic leukemia and their putative normal counterparts in human fetal hematopoietic tissues. Blood. 1989 Mar;73(4):1000–1015. [PubMed] [Google Scholar]
  22. Uckun F. M., Myers D. E., Ledbetter J. A., Swaim S. E., Gajl-Peczalska K. J., Vallera D. A. Use of colony assays and anti-T cell immunotoxins to elucidate the immunobiologic features of leukemic progenitor cells in T-lineage acute lymphoblastic leukemia. J Immunol. 1988 Mar 15;140(6):2103–2111. [PubMed] [Google Scholar]
  23. Veillette A., Bookman M. A., Horak E. M., Bolen J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell. 1988 Oct 21;55(2):301–308. doi: 10.1016/0092-8674(88)90053-0. [DOI] [PubMed] [Google Scholar]
  24. Veillette A., Zúiga-Pflücker J. C., Bolen J. B., Kruisbeek A. M. Engagement of CD4 and CD8 expressed on immature thymocytes induces activation of intracellular tyrosine phosphorylation pathways. J Exp Med. 1989 Nov 1;170(5):1671–1680. doi: 10.1084/jem.170.5.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Welch P. A., Namen A. E., Goodwin R. G., Armitage R., Cooper M. D. Human IL-7: a novel T cell growth factor. J Immunol. 1989 Dec 1;143(11):3562–3567. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES