Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Aug 1;184(2):325–336. doi: 10.1084/jem.184.2.325

Differential effects of interleukin-15 and interleukin-2 on differentiation of bipotential T/natural killer progenitor cells

PMCID: PMC2192730  PMID: 8760786

Abstract

Bipotential T/natural killer (NK) progenitor cells are destined to differentiate mainly into T cell receptor (TCR) alpha beta and TCR gamma delta cells in a thymic microenvironment, whereas extrathymically they selectively develop into NK cells. The exact environmental conditions that are required for differentiation into these three leukocyte populations are largely unknown. In this report, we have investigated and compared the effect of interleukin (IL)-15 and IL-2 in this process. The IL-15 receptor is composed of the gamma and beta chains of the IL-2 receptor (IL-2R gamma and IL-2R beta) and of a specific alpha chain (IL-15R alpha). Here, it is shown that IL-15 mRNA is mainly expressed in thymic epithelial stromal cells, whereas IL-2 mRNA is exclusively expressed in thymocytes. IL-2R beta-expressing cells were present in the fetal thymus with a CD25-CD44+Fc gamma R+HSA- /low TCR- phenotype, which is characteristic of progenitor cells. These cells also expressed IL-15R alpha messenger RNA. Sorted IL-2R beta + TCR- cells differentiated into TCR alpha beta and TCR gamma delta cells after transfer to alymphoid thymic lobes, whereas culture of the same sorted cells in cell suspension in the presence of IL-15 resulted in the generation of functional NK cells. This shows that IL-2R beta +TCR- cells of the fetal thymus contain bipotential T/NK progenitors. Addition of low concentrations of IL-15 to fetal thymic organ culture (FTOC) resulted in an increase of all T cell subpopulations. The largest expansion occurred in the TCR gamma delta compartment. In contrast, low concentrations of IL-2 did not result in a higher total cell number and did not induce outgrowth of TCR gamma delta cells. High concentrations of IL-15 blocked TCR alpha beta development and shifted differentiation towards NK cells. Differentiation towards TCR gamma delta cells still proceeded. High concentrations of IL-2 similarly induced development into NK cells, but the cell number was fourfold lower than in IL-15 cultures. Importantly, blocking of IL-2R alpha in IL-2-treated FTOC resulted in a drastic increase in cell number, indicating that IL-2R alpha negatively regulates cell expansion. Collectively, these experiments provide direct evidence that IL-15 and IL-2 differentially affect the differentiation of bipotential T/NK progenitors.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Anderson G., Jenkinson E. J., Moore N. C., Owen J. J. MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature. 1993 Mar 4;362(6415):70–73. doi: 10.1038/362070a0. [DOI] [PubMed] [Google Scholar]
  2. Anderson G., Owen J. J., Moore N. C., Jenkinson E. J. Thymic epithelial cells provide unique signals for positive selection of CD4+CD8+ thymocytes in vitro. J Exp Med. 1994 Jun 1;179(6):2027–2031. doi: 10.1084/jem.179.6.2027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ardavin C., Wu L., Li C. L., Shortman K. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature. 1993 Apr 22;362(6422):761–763. doi: 10.1038/362761a0. [DOI] [PubMed] [Google Scholar]
  4. Armitage R. J., Macduff B. M., Eisenman J., Paxton R., Grabstein K. H. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol. 1995 Jan 15;154(2):483–490. [PubMed] [Google Scholar]
  5. Bazan J. F. Unraveling the structure of IL-2. Science. 1992 Jul 17;257(5068):410–413. doi: 10.1126/science.1631562. [DOI] [PubMed] [Google Scholar]
  6. Bhatia S. K., Tygrett L. T., Grabstein K. H., Waldschmidt T. J. The effect of in vivo IL-7 deprivation on T cell maturation. J Exp Med. 1995 Apr 1;181(4):1399–1409. doi: 10.1084/jem.181.4.1399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carson W. E., Giri J. G., Lindemann M. J., Linett M. L., Ahdieh M., Paxton R., Anderson D., Eisenmann J., Grabstein K., Caligiuri M. A. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994 Oct 1;180(4):1395–1403. doi: 10.1084/jem.180.4.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chun J. J., Schatz D. G., Oettinger M. A., Jaenisch R., Baltimore D. The recombination activating gene-1 (RAG-1) transcript is present in the murine central nervous system. Cell. 1991 Jan 11;64(1):189–200. doi: 10.1016/0092-8674(91)90220-s. [DOI] [PubMed] [Google Scholar]
  9. DiSanto J. P., Müller W., Guy-Grand D., Fischer A., Rajewsky K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):377–381. doi: 10.1073/pnas.92.2.377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Falk I., Levelt C. N., Eichmann K. Lineage relationships of the fetal thymocyte subset that expresses the beta chain of the interleukin-2 receptor. Eur J Immunol. 1993 Dec;23(12):3373–3376. doi: 10.1002/eji.1830231248. [DOI] [PubMed] [Google Scholar]
  11. Galy A., Verma S., Bárcena A., Spits H. Precursors of CD3+CD4+CD8+ cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development. J Exp Med. 1993 Aug 1;178(2):391–401. doi: 10.1084/jem.178.2.391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Giri J. G., Kumaki S., Ahdieh M., Friend D. J., Loomis A., Shanebeck K., DuBose R., Cosman D., Park L. S., Anderson D. M. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J. 1995 Aug 1;14(15):3654–3663. doi: 10.1002/j.1460-2075.1995.tb00035.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Godfrey D. I., Kennedy J., Suda T., Zlotnik A. A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J Immunol. 1993 May 15;150(10):4244–4252. [PubMed] [Google Scholar]
  15. Grabstein K. H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M. A., Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. doi: 10.1126/science.8178155. [DOI] [PubMed] [Google Scholar]
  16. Grabstein K. H., Waldschmidt T. J., Finkelman F. D., Hess B. W., Alpert A. R., Boiani N. E., Namen A. E., Morrissey P. J. Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody. J Exp Med. 1993 Jul 1;178(1):257–264. doi: 10.1084/jem.178.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hackett J., Jr, Bosma G. C., Bosma M. J., Bennett M., Kumar V. Transplantable progenitors of natural killer cells are distinct from those of T and B lymphocytes. Proc Natl Acad Sci U S A. 1986 May;83(10):3427–3431. doi: 10.1073/pnas.83.10.3427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hanke T., Mitnacht R., Boyd R., Hünig T. Induction of interleukin 2 receptor beta chain expression by self-recognition in the thymus. J Exp Med. 1994 Nov 1;180(5):1629–1636. doi: 10.1084/jem.180.5.1629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Havran W. L., Allison J. P. Origin of Thy-1+ dendritic epidermal cells of adult mice from fetal thymic precursors. Nature. 1990 Mar 1;344(6261):68–70. doi: 10.1038/344068a0. [DOI] [PubMed] [Google Scholar]
  20. Kimura Y., Takeshita T., Kondo M., Ishii N., Nakamura M., Van Snick J., Sugamura K. Sharing of the IL-2 receptor gamma chain with the functional IL-9 receptor complex. Int Immunol. 1995 Jan;7(1):115–120. doi: 10.1093/intimm/7.1.115. [DOI] [PubMed] [Google Scholar]
  21. Kondo M., Takeshita T., Ishii N., Nakamura M., Watanabe S., Arai K., Sugamura K. Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science. 1993 Dec 17;262(5141):1874–1877. doi: 10.1126/science.8266076. [DOI] [PubMed] [Google Scholar]
  22. Kühn R., Rajewsky K., Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. doi: 10.1126/science.1948049. [DOI] [PubMed] [Google Scholar]
  23. Kündig T. M., Schorle H., Bachmann M. F., Hengartner H., Zinkernagel R. M., Horak I. Immune responses in interleukin-2-deficient mice. Science. 1993 Nov 12;262(5136):1059–1061. doi: 10.1126/science.8235625. [DOI] [PubMed] [Google Scholar]
  24. Lanier L. L., Spits H., Phillips J. H. The developmental relationship between NK cells and T cells. Immunol Today. 1992 Oct;13(10):392–395. doi: 10.1016/0167-5699(92)90087-N. [DOI] [PubMed] [Google Scholar]
  25. Leclercq G., De Smedt M., Plum J. Cytokine dependence of V gamma 3 thymocytes: mature but not immature V gamma 3 cells require endogenous IL-2 and IL-7 to survive--evidence for cytokine redundancy. Int Immunol. 1995 May;7(5):843–851. doi: 10.1093/intimm/7.5.843. [DOI] [PubMed] [Google Scholar]
  26. Leclercq G., Plum J. Developmentally ordered appearance of a functional Fc gamma receptor on TCR V gamma 3 thymocytes. Evidence for stimulation-induced expression. J Immunol. 1994 Sep 15;153(6):2429–2435. [PubMed] [Google Scholar]
  27. Leclercq G., Plum J., Nandi D., De Smedt M., Allison J. P. Intrathymic differentiation of V gamma 3 T cells. J Exp Med. 1993 Jul 1;178(1):309–315. doi: 10.1084/jem.178.1.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Matsuzaki Y., Gyotoku J., Ogawa M., Nishikawa S., Katsura Y., Gachelin G., Nakauchi H. Characterization of c-kit positive intrathymic stem cells that are restricted to lymphoid differentiation. J Exp Med. 1993 Oct 1;178(4):1283–1292. doi: 10.1084/jem.178.4.1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Miller J. S., Alley K. A., McGlave P. Differentiation of natural killer (NK) cells from human primitive marrow progenitors in a stroma-based long-term culture system: identification of a CD34+7+ NK progenitor. Blood. 1994 May 1;83(9):2594–2601. [PubMed] [Google Scholar]
  30. Miller J. S., Verfaillie C., McGlave P. The generation of human natural killer cells from CD34+/DR- primitive progenitors in long-term bone marrow culture. Blood. 1992 Nov 1;80(9):2182–2187. [PubMed] [Google Scholar]
  31. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  32. Nishimura H., Hiromatsu K., Kobayashi N., Grabstein K. H., Paxton R., Sugamura K., Bluestone J. A., Yoshikai Y. IL-15 is a novel growth factor for murine gamma delta T cells induced by Salmonella infection. J Immunol. 1996 Jan 15;156(2):663–669. [PubMed] [Google Scholar]
  33. 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]
  34. 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]
  35. Noguchi M., Yi H., Rosenblatt H. M., Filipovich A. H., Adelstein S., Modi W. S., McBride O. W., Leonard W. J. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147–157. doi: 10.1016/0092-8674(93)90167-o. [DOI] [PubMed] [Google Scholar]
  36. Park J. H., Mitnacht R., Torres-Nagel N., Hünig T. T cell receptor ligation induces interleukin (IL) 2R beta chain expression in rat CD4,8 double positive thymocytes, initiating an IL-2-dependent differentiation pathway of CD8 alpha+/beta- T cells. J Exp Med. 1993 Feb 1;177(2):541–546. doi: 10.1084/jem.177.2.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Peschon J. J., Morrissey P. J., Grabstein K. H., Ramsdell F. J., Maraskovsky E., Gliniak B. C., Park L. S., Ziegler S. F., Williams D. E., Ware C. B. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994 Nov 1;180(5):1955–1960. doi: 10.1084/jem.180.5.1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Plum J., De Smedt M., Leclercq G., Vandekerckhove B. Influence of TGF-beta on murine thymocyte development in fetal thymus organ culture. J Immunol. 1995 Jun 1;154(11):5789–5798. [PubMed] [Google Scholar]
  39. Rodewald H. R., Awad K., Moingeon P., D'Adamio L., Rabinowitz D., Shinkai Y., Alt F. W., Reinherz E. L. Fc gamma RII/III and CD2 expression mark distinct subpopulations of immature CD4-CD8- murine thymocytes: in vivo developmental kinetics and T cell receptor beta chain rearrangement status. J Exp Med. 1993 Apr 1;177(4):1079–1092. doi: 10.1084/jem.177.4.1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rodewald H. R., Moingeon P., Lucich J. L., Dosiou C., Lopez P., Reinherz E. L. A population of early fetal thymocytes expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells. Cell. 1992 Apr 3;69(1):139–150. doi: 10.1016/0092-8674(92)90125-v. [DOI] [PubMed] [Google Scholar]
  41. Russell S. M., Keegan A. D., Harada N., Nakamura Y., Noguchi M., Leland P., Friedmann M. C., Miyajima A., Puri R. K., Paul W. E. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993 Dec 17;262(5141):1880–1883. doi: 10.1126/science.8266078. [DOI] [PubMed] [Google Scholar]
  42. Sadlack B., Kühn R., Schorle H., Rajewsky K., Müller W., Horak I. Development and proliferation of lymphocytes in mice deficient for both interleukins-2 and -4. Eur J Immunol. 1994 Jan;24(1):281–284. doi: 10.1002/eji.1830240144. [DOI] [PubMed] [Google Scholar]
  43. Schorle H., Holtschke T., Hünig T., Schimpl A., Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature. 1991 Aug 15;352(6336):621–624. doi: 10.1038/352621a0. [DOI] [PubMed] [Google Scholar]
  44. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  45. Smith K. A. Interleukin-2: inception, impact, and implications. Science. 1988 May 27;240(4856):1169–1176. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
  46. Spits H., Lanier L. L., Phillips J. H. Development of human T and natural killer cells. Blood. 1995 May 15;85(10):2654–2670. [PubMed] [Google Scholar]
  47. Suzuki H., Kündig T. M., Furlonger C., Wakeham A., Timms E., Matsuyama T., Schmits R., Simard J. J., Ohashi P. S., Griesser H. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science. 1995 Jun 9;268(5216):1472–1476. doi: 10.1126/science.7770771. [DOI] [PubMed] [Google Scholar]
  48. Sánchez M. J., Muench M. O., Roncarolo M. G., Lanier L. L., Phillips J. H. Identification of a common T/natural killer cell progenitor in human fetal thymus. J Exp Med. 1994 Aug 1;180(2):569–576. doi: 10.1084/jem.180.2.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sánchez M. J., Spits H., Lanier L. L., Phillips J. H. Human natural killer cell committed thymocytes and their relation to the T cell lineage. J Exp Med. 1993 Dec 1;178(6):1857–1866. doi: 10.1084/jem.178.6.1857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Tanaka T., Kitamura F., Nagasaka Y., Kuida K., Suwa H., Miyasaka M. Selective long-term elimination of natural killer cells in vivo by an anti-interleukin 2 receptor beta chain monoclonal antibody in mice. J Exp Med. 1993 Sep 1;178(3):1103–1107. doi: 10.1084/jem.178.3.1103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tanaka T., Takeuchi Y., Shiohara T., Kitamura F., Nagasaka Y., Hamamura K., Yagita H., Miyasaka M. In utero treatment with monoclonal antibody to IL-2 receptor beta-chain completely abrogates development of Thy-1+ dendritic epidermal cells. Int Immunol. 1992 Apr;4(4):487–491. doi: 10.1093/intimm/4.4.487. [DOI] [PubMed] [Google Scholar]
  52. Wang B., Biron C., She J., Higgins K., Sunshine M. J., Lacy E., Lonberg N., Terhorst C. A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3E gene. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9402–9406. doi: 10.1073/pnas.91.20.9402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wilkinson P. C., Liew F. Y. Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med. 1995 Mar 1;181(3):1255–1259. doi: 10.1084/jem.181.3.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Willerford D. M., Chen J., Ferry J. A., Davidson L., Ma A., Alt F. W. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity. 1995 Oct;3(4):521–530. doi: 10.1016/1074-7613(95)90180-9. [DOI] [PubMed] [Google Scholar]
  55. de Jong J. L., Farner N. L., Widmer M. B., Giri J. G., Sondel P. M. Interaction of IL-15 with the shared IL-2 receptor beta and gamma c subunits. The IL-15/beta/gamma c receptor-ligand complex is less stable than the IL-2/beta/gamma c receptor-ligand complex. J Immunol. 1996 Feb 15;156(4):1339–1348. [PubMed] [Google Scholar]
  56. von Freeden-Jeffry U., Vieira P., Lucian L. A., McNeil T., Burdach S. E., Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med. 1995 Apr 1;181(4):1519–1526. doi: 10.1084/jem.181.4.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES