Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1990 Aug 1;172(2):577–587. doi: 10.1084/jem.172.2.577

Interleukin 7 enhances cytolytic T lymphocyte generation and induces lymphokine-activated killer cells from human peripheral blood

PMCID: PMC2188337  PMID: 2142722

Abstract

The effects of purified recombinant interleukin 7 (IL-7) on the generation of cytolytic T lymphocytes (CTL) in mixed lymphocyte culture (MLC) and on the induction of lymphokine-activated killer (LAK) cells in autologous cultures of human peripheral blood mononuclear cells were investigated. IL-7 was found to induce the generation of both CTL and LAK cells in bulk cultures. The appearance of peak CTL activity in MLC established with exogenous IL-7 was delayed in comparison with replicate cultures containing exogenous IL-2, but both cytokines stimulated quantitatively similar levels of antigen-specific lytic activity. An IL-2-neutralizing antiserum inhibited substantially, but not completely, the effect of IL-7 on CTL generation, implying the existence of both an indirect component of IL-7 activity via IL-2 utilization, as well as an IL-2-independent component. Cell surface phenotypic analysis of IL-2- or IL-7-generated CTL effector cells revealed that CD8+ cells were responsible for the vast majority of lytic activity. Limiting dilution analysis (LDA) revealed that essentially identical frequencies of CTL precursors (CTL-P) were capable of clonal expansion and/or differentiation in the presence of exogenous IL-2, IL-4, or IL-7, supporting the concept that all three of these cytokines are capable of exerting a major influence on T cell growth and differentiation. Approximately half of the CTL-P that responded in IL-7-supplemented LDA cultures did so in an IL-2- independent manner. IL-7 stimulated the development of LAK cells in autologous bulk cultures, but only weakly in comparison with IL-2. In contrast to its effects on CTL generation, the induction of LAK cells by IL-7 was virtually independent of IL-2. LAK cells induced by IL-7, like those induced by IL-2, were phenotypically heterogeneous and included CD8+, CD56+, and gamma/delta+ cells. Limiting dilution analysis indicated that IL-2 stimulated fivefold more LAK-P than IL-7 and 220-fold more than IL-4. Collectively, these data suggest that IL-7 has potent regulatory effects on human cytolytic cell populations and, either alone or in combination with other cytokines, could be important for the in vitro expansion of cells for adoptive immunotherapy.

Full Text

The Full Text of this article is available as a PDF (1,010.8 KB).

Selected References

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

  1. Aoki T., Kikuchi H., Miyatake S., Oda Y., Iwasaki K., Yamasaki T., Kinashi T., Honjo T. Interleukin 5 enhances interleukin 2-mediated lymphokine-activated killer activity. J Exp Med. 1989 Aug 1;170(2):583–588. doi: 10.1084/jem.170.2.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Borst J., van de Griend R. J., van Oostveen J. W., Ang S. L., Melief C. J., Seidman J. G., Bolhuis R. L. A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes. Nature. 1987 Feb 19;325(6106):683–688. doi: 10.1038/325683a0. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Grimm E. A., Mazumder A., Zhang H. Z., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982 Jun 1;155(6):1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hochuli E., Döbeli H., Schacher A. New metal chelate adsorbent selective for proteins and peptides containing neighbouring histidine residues. J Chromatogr. 1987 Dec 18;411:177–184. doi: 10.1016/s0021-9673(00)93969-4. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Kawakami Y., Custer M. C., Rosenberg S. A., Lotze M. T. IL-4 regulates IL-2 induction of lymphokine-activated killer activity from human lymphocytes. J Immunol. 1989 May 15;142(10):3452–3461. [PubMed] [Google Scholar]
  12. Koide J., Rivas A., Engleman E. G. Natural killer (NK)-like cytotoxic activity of allospecific T cell receptor-gamma,delta+ T cell clones. Distinct receptor-ligand interactions mediate NK-like and allospecific cytotoxicity. J Immunol. 1989 Jun 15;142(12):4161–4168. [PubMed] [Google Scholar]
  13. Luger T. A., Krutmann J., Kirnbauer R., Urbanski A., Schwarz T., Klappacher G., Köck A., Micksche M., Malejczyk J., Schauer E. IFN-beta 2/IL-6 augments the activity of human natural killer cells. J Immunol. 1989 Aug 15;143(4):1206–1209. [PubMed] [Google Scholar]
  14. Meuer S. C., Hussey R. E., Cantrell D. A., Hodgdon J. C., Schlossman S. F., Smith K. A., Reinherz E. L. Triggering of the T3-Ti antigen-receptor complex results in clonal T-cell proliferation through an interleukin 2-dependent autocrine pathway. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1509–1513. doi: 10.1073/pnas.81.5.1509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Moingeon P., Jitsukawa S., Faure F., Troalen F., Triebel F., Graziani M., Forestier F., Bellet D., Bohuon C., Hercend T. A gamma-chain complex forms a functional receptor on cloned human lymphocytes with natural killer-like activity. Nature. 1987 Feb 19;325(6106):723–726. doi: 10.1038/325723a0. [DOI] [PubMed] [Google Scholar]
  16. Moretta L., Pende D., Cozzani R., Merli A., Bagnasco M., Mingari M. C. T cell nature of some lymphokine-activated killer (LAK) cells. Frequency analysis of LAK precursors within human T cell populations and clonal analysis of LAK effector cells. Eur J Immunol. 1986 Dec;16(12):1623–1625. doi: 10.1002/eji.1830161224. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Nagler A., Lanier L. L., Phillips J. H. The effects of IL-4 on human natural killer cells. A potent regulator of IL-2 activation and proliferation. J Immunol. 1988 Oct 1;141(7):2349–2351. [PubMed] [Google Scholar]
  19. 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]
  20. Ortaldo J. R., Mason A., Overton R. Lymphokine-activated killer cells. Analysis of progenitors and effectors. J Exp Med. 1986 Oct 1;164(4):1193–1205. doi: 10.1084/jem.164.4.1193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Paliard X., Yssel H., Blanchard D., Waitz J. A., deVries J. E., Spits H. Antigen specific and MHC nonrestricted cytotoxicity of T cell receptor alpha beta+ and gamma delta+ human T cell clones isolated in IL-4. J Immunol. 1989 Jul 15;143(2):452–457. [PubMed] [Google Scholar]
  22. Phillips J. H., Lanier L. L. Dissection of the lymphokine-activated killer phenomenon. Relative contribution of peripheral blood natural killer cells and T lymphocytes to cytolysis. J Exp Med. 1986 Sep 1;164(3):814–825. doi: 10.1084/jem.164.3.814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Spits H., Yssel H., Paliard X., Kastelein R., Figdor C., de Vries J. E. IL-4 inhibits IL-2-mediated induction of human lymphokine-activated killer cells, but not the generation of antigen-specific cytotoxic T lymphocytes in mixed leukocyte cultures. J Immunol. 1988 Jul 1;141(1):29–36. [PubMed] [Google Scholar]
  24. Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]
  25. Urdal D. L., Mochizuki D., Conlon P. J., March C. J., Remerowski M. L., Eisenman J., Ramthun C., Gillis S. Lymphokine purification by reversed-phase high-performance liquid chromatography. J Chromatogr. 1984 Jul 27;296:171–179. doi: 10.1016/s0021-9673(01)96410-6. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Yokota S., Geppert T. D., Lipsky P. E. Enhancement of antigen- and mitogen-induced human T lymphocyte proliferation by tumor necrosis factor-alpha. J Immunol. 1988 Jan 15;140(2):531–536. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES