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. 1996 Sep 16;15(18):4928–4939.

Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells.

Y Tagaya 1, J D Burton 1, Y Miyamoto 1, T A Waldmann 1
PMCID: PMC452230  PMID: 8890166

Abstract

Interleukin-15/T(IL-15) is a growth factor that utilizes IL-2 receptor (IL-2R) components in addition to its private binding protein IL-15R(alpha) in T-cells. Here, we report that IL-15 induces mast cell proliferation in the absence of IL-2R alpha and beta. Using transfectants of these cells with a cytoplasmic-truncated mutant of gamma(c), we demonstrated that IL-15 signaling in mast cells does not involve gamma(c). Cross-linking of mast cells with [(125)I]IL-15 revealed a 60-65 kDa IL-15 binding protein that is distinct from known components of T-cell IL-15 receptors. Mast cell IL-15 receptors recruit JAK-2 and STAT-5, instead of JAK1/3 and STAT3/5 that are activated in T-cells. Thus IL-15 is a mast cell growth factor that utilizes a novel receptor and distinct signaling pathway.

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Selected References

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

  1. Anderson D. M., Johnson L., Glaccum M. B., Copeland N. G., Gilbert D. J., Jenkins N. A., Valentine V., Kirstein M. N., Shapiro D. N., Morris S. W. Chromosomal assignment and genomic structure of Il15. Genomics. 1995 Feb 10;25(3):701–706. doi: 10.1016/0888-7543(95)80013-c. [DOI] [PubMed] [Google Scholar]
  2. Anderson D. M., Kumaki S., Ahdieh M., Bertles J., Tometsko M., Loomis A., Giri J., Copeland N. G., Gilbert D. J., Jenkins N. A. Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes. J Biol Chem. 1995 Dec 15;270(50):29862–29869. doi: 10.1074/jbc.270.50.29862. [DOI] [PubMed] [Google Scholar]
  3. Argetsinger L. S., Campbell G. S., Yang X., Witthuhn B. A., Silvennoinen O., Ihle J. N., Carter-Su C. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell. 1993 Jul 30;74(2):237–244. doi: 10.1016/0092-8674(93)90415-m. [DOI] [PubMed] [Google Scholar]
  4. Bamford R. N., Battiata A. P., Burton J. D., Sharma H., Waldmann T. A. Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I region /IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2897–2902. doi: 10.1073/pnas.93.7.2897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bamford R. N., Grant A. J., Burton J. D., Peters C., Kurys G., Goldman C. K., Brennan J., Roessler E., Waldmann T. A. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4940–4944. doi: 10.1073/pnas.91.11.4940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beadling C., Guschin D., Witthuhn B. A., Ziemiecki A., Ihle J. N., Kerr I. M., Cantrell D. A. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. EMBO J. 1994 Dec 1;13(23):5605–5615. doi: 10.1002/j.1460-2075.1994.tb06898.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burton J. D., Bamford R. N., Peters C., Grant A. J., Kurys G., Goldman C. K., Brennan J., Roessler E., Waldmann T. A. A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4935–4939. doi: 10.1073/pnas.91.11.4935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cao X., Shores E. W., Hu-Li J., Anver M. R., Kelsall B. L., Russell S. M., Drago J., Noguchi M., Grinberg A., Bloom E. T. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity. 1995 Mar;2(3):223–238. doi: 10.1016/1074-7613(95)90047-0. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Dusanter-Fourt I., Muller O., Ziemiecki A., Mayeux P., Drucker B., Djiane J., Wilks A., Harpur A. G., Fischer S., Gisselbrecht S. Identification of JAK protein tyrosine kinases as signaling molecules for prolactin. Functional analysis of prolactin receptor and prolactin-erythropoietin receptor chimera expressed in lymphoid cells. EMBO J. 1994 Jun 1;13(11):2583–2591. doi: 10.1002/j.1460-2075.1994.tb06548.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  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. Ivashkiv L. B. Cytokines and STATs: how can signals achieve specificity? Immunity. 1995 Jul;3(1):1–4. doi: 10.1016/1074-7613(95)90152-3. [DOI] [PubMed] [Google Scholar]
  17. Johnston J. A., Kawamura M., Kirken R. A., Chen Y. Q., Blake T. B., Shibuya K., Ortaldo J. R., McVicar D. W., O'Shea J. J. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994 Jul 14;370(6485):151–153. doi: 10.1038/370151a0. [DOI] [PubMed] [Google Scholar]
  18. Johnston J. A., Wang L. M., Hanson E. P., Sun X. J., White M. F., Oakes S. A., Pierce J. H., O'Shea J. J. Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. J Biol Chem. 1995 Dec 1;270(48):28527–28530. doi: 10.1074/jbc.270.48.28527. [DOI] [PubMed] [Google Scholar]
  19. Kawahara A., Minami Y., Taniguchi T. Evidence for a critical role for the cytoplasmic region of the interleukin 2 (IL-2) receptor gamma chain in IL-2, IL-4, and IL-7 signalling. Mol Cell Biol. 1994 Aug;14(8):5433–5440. doi: 10.1128/mcb.14.8.5433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994 Jan 28;76(2):253–262. doi: 10.1016/0092-8674(94)90333-6. [DOI] [PubMed] [Google Scholar]
  21. Kitamura T., Sato N., Arai K., Miyajima A. Expression cloning of the human IL-3 receptor cDNA reveals a shared beta subunit for the human IL-3 and GM-CSF receptors. Cell. 1991 Sep 20;66(6):1165–1174. doi: 10.1016/0092-8674(91)90039-2. [DOI] [PubMed] [Google Scholar]
  22. Lin J. X., Migone T. S., Tsang M., Friedmann M., Weatherbee J. A., Zhou L., Yamauchi A., Bloom E. T., Mietz J., John S. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995 Apr;2(4):331–339. doi: 10.1016/1074-7613(95)90141-8. [DOI] [PubMed] [Google Scholar]
  23. Malek T. R., Furse R. K., Fleming M. L., Fadell A. J., He Y. W. Biochemical identity and characterization of the mouse interleukin-2 receptor beta and gamma c subunits. J Interferon Cytokine Res. 1995 May;15(5):447–454. doi: 10.1089/jir.1995.15.447. [DOI] [PubMed] [Google Scholar]
  24. Miyazaki T., Liu Z. J., Kawahara A., Minami Y., Yamada K., Tsujimoto Y., Barsoumian E. L., Permutter R. M., Taniguchi T. Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Cell. 1995 Apr 21;81(2):223–231. doi: 10.1016/0092-8674(95)90332-1. [DOI] [PubMed] [Google Scholar]
  25. Mizushima S., Nagata S. pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 1990 Sep 11;18(17):5322–5322. doi: 10.1093/nar/18.17.5322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Oakley B. R., Kirsch D. R., Morris N. R. A simplified ultrasensitive silver stain for detecting proteins in polyacrylamide gels. Anal Biochem. 1980 Jul 1;105(2):361–363. doi: 10.1016/0003-2697(80)90470-4. [DOI] [PubMed] [Google Scholar]
  27. Otani H., Siegel J. P., Erdos M., Gnarra J. R., Toledano M. B., Sharon M., Mostowski H., Feinberg M. B., Pierce J. H., Leonard W. J. Interleukin (IL)-2 and IL-3 induce distinct but overlapping responses in murine IL-3-dependent 32D cells transduced with human IL-2 receptor beta chain: involvement of tyrosine kinase(s) other than p56lck. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2789–2793. doi: 10.1073/pnas.89.7.2789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Paul W. E., Seder R. A., Plaut M. Lymphokine and cytokine production by Fc epsilon RI+ cells. Adv Immunol. 1993;53:1–29. [PubMed] [Google Scholar]
  29. Plaut M., Pierce J. H., Watson C. J., Hanley-Hyde J., Nordan R. P., Paul W. E. Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI or to calcium ionophores. Nature. 1989 May 4;339(6219):64–67. doi: 10.1038/339064a0. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Taniguchi T. Cytokine signaling through nonreceptor protein tyrosine kinases. Science. 1995 Apr 14;268(5208):251–255. doi: 10.1126/science.7716517. [DOI] [PubMed] [Google Scholar]
  32. Taniguchi T., Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell. 1993 Apr 9;73(1):5–8. doi: 10.1016/0092-8674(93)90152-g. [DOI] [PubMed] [Google Scholar]
  33. Tavernier J., Devos R., Cornelis S., Tuypens T., Van der Heyden J., Fiers W., Plaetinck G. A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF. Cell. 1991 Sep 20;66(6):1175–1184. doi: 10.1016/0092-8674(91)90040-6. [DOI] [PubMed] [Google Scholar]
  34. Vogt P. K., Bos T. J. jun: oncogene and transcription factor. Adv Cancer Res. 1990;55:1–35. doi: 10.1016/s0065-230x(08)60466-2. [DOI] [PubMed] [Google Scholar]
  35. Waldmann T. A. The multi-subunit interleukin-2 receptor. Annu Rev Biochem. 1989;58:875–911. doi: 10.1146/annurev.bi.58.070189.004303. [DOI] [PubMed] [Google Scholar]
  36. Witthuhn B. A., Quelle F. W., Silvennoinen O., Yi T., Tang B., Miura O., Ihle J. N. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993 Jul 30;74(2):227–236. doi: 10.1016/0092-8674(93)90414-l. [DOI] [PubMed] [Google Scholar]
  37. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994 Jul 14;370(6485):153–157. doi: 10.1038/370153a0. [DOI] [PubMed] [Google Scholar]

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