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
. 1993 Dec 1;90(23):10984–10988. doi: 10.1073/pnas.90.23.10984

Expression of nerve growth factor and nerve growth factor receptor tyrosine kinase Trk in activated CD4-positive T-cell clones.

P B Ehrhard 1, P Erb 1, U Graumann 1, U Otten 1
PMCID: PMC47906  PMID: 7902578

Abstract

Recent evidence suggests that nerve growth factor (NGF), in addition to its neurotrophic functions, acts as an immunomodulator mediating "cross-talk" between neuronal and immune cells, including T lymphocytes. We have analyzed murine CD4+ T-cell clones for their ability to express transcripts encoding NGF, low-affinity NGF receptor, and trk protooncogene, the signal-transducing receptor subunit for NGF. We show that two CD4+ T-helper (Th) clones, Th0-type clone 8/37 and Th2-type clone D10.G4.1, express NGF and Trk mRNA after appropriate activation with mitogen or with antigen and antigen-presenting cells. NGF and trk induction occurred to a similar extent and over a similar time course in activated 8/37 T cells, raising the possibility that NGF and trk genes are under coordinate control. NGF and NGF receptor expression does not seem to be a universal property of all activated CD4+ T cells, since Th1-type clone 9/9 did not express any of the transcripts after either stimulation. The absence of low-affinity NGF receptor mRNA in resting and activated T cells implies that the low-affinity NGF receptor is not involved in NGF signal transduction in CD4+ T cells. Our finding that activated CD4+ T-cell clones not only express Trk but also synthesize and release biologically active NGF implicates NGF as an autocrine and/or paracrine factor in the development and regulation of immune responses.

Full text

PDF
10984

Images in this article

Selected References

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

  1. Ayane M., Nielsen P., Köhler G. Cloning and sequencing of mouse ribosomal protein S12 cDNA. Nucleic Acids Res. 1989 Aug 25;17(16):6722–6722. doi: 10.1093/nar/17.16.6722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Banks B. E. Nerve growth factor--an enigma still? Biochem Soc Trans. 1984 Apr;12(2):173–176. doi: 10.1042/bst0120173. [DOI] [PubMed] [Google Scholar]
  3. Birren S. J., Verdi J. M., Anderson D. J. Membrane depolarization induces p140trk and NGF responsiveness, but not p75LNGFR, in MAH cells. Science. 1992 Jul 17;257(5068):395–397. doi: 10.1126/science.1321502. [DOI] [PubMed] [Google Scholar]
  4. Brodie C., Gelfand E. W. Functional nerve growth factor receptors on human B lymphocytes. Interaction with IL-2. J Immunol. 1992 Jun 1;148(11):3492–3497. [PubMed] [Google Scholar]
  5. Bruni A., Bigon E., Boarato E., Mietto L., Leon A., Toffano G. Interaction between nerve growth factor and lysophosphatidylserine on rat peritoneal mast cells. FEBS Lett. 1982 Feb 22;138(2):190–192. doi: 10.1016/0014-5793(82)80438-9. [DOI] [PubMed] [Google Scholar]
  6. Chao M. V. Neurotrophin receptors: a window into neuronal differentiation. Neuron. 1992 Oct;9(4):583–593. doi: 10.1016/0896-6273(92)90023-7. [DOI] [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Cordon-Cardo C., Tapley P., Jing S. Q., Nanduri V., O'Rourke E., Lamballe F., Kovary K., Klein R., Jones K. R., Reichardt L. F. The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3. Cell. 1991 Jul 12;66(1):173–183. doi: 10.1016/0092-8674(91)90149-s. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ehrhard P. B., Ganter U., Stalder A., Bauer J., Otten U. Expression of functional trk protooncogene in human monocytes. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5423–5427. doi: 10.1073/pnas.90.12.5423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Erb P., Troxler M., Fluri M., Grogg D., Alkan S. S. Functional heterogeneity of CD4-positive T-cell subsets: the correlation between effector functions and lymphokine secretion is limited. Cell Immunol. 1991 Jun;135(1):232–244. doi: 10.1016/0008-8749(91)90268-g. [DOI] [PubMed] [Google Scholar]
  11. Frei K., Malipiero U. V., Leist T. P., Zinkernagel R. M., Schwab M. E., Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol. 1989 Apr;19(4):689–694. doi: 10.1002/eji.1830190418. [DOI] [PubMed] [Google Scholar]
  12. Furukawa S., Furukawa Y., Satoyoshi E., Hayashi K. Synthesis and secretion of nerve growth factor by mouse astroglial cells in culture. Biochem Biophys Res Commun. 1986 Apr 14;136(1):57–63. doi: 10.1016/0006-291x(86)90876-4. [DOI] [PubMed] [Google Scholar]
  13. Gadient R. A., Cron K. C., Otten U. Interleukin-1 beta and tumor necrosis factor-alpha synergistically stimulate nerve growth factor (NGF) release from cultured rat astrocytes. Neurosci Lett. 1990 Sep 18;117(3):335–340. doi: 10.1016/0304-3940(90)90687-5. [DOI] [PubMed] [Google Scholar]
  14. Green S. H., Rydel R. E., Connolly J. L., Greene L. A. PC12 cell mutants that possess low- but not high-affinity nerve growth factor receptors neither respond to nor internalize nerve growth factor. J Cell Biol. 1986 Mar;102(3):830–843. doi: 10.1083/jcb.102.3.830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Greene L. A., Tischler A. S. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2424–2428. doi: 10.1073/pnas.73.7.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hempstead B. L., Martin-Zanca D., Kaplan D. R., Parada L. F., Chao M. V. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678–683. doi: 10.1038/350678a0. [DOI] [PubMed] [Google Scholar]
  17. Heumann R., Lindholm D., Bandtlow C., Meyer M., Radeke M. J., Misko T. P., Shooter E., Thoenen H. Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8735–8739. doi: 10.1073/pnas.84.23.8735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Holtzman D. M., Li Y., Parada L. F., Kinsman S., Chen C. K., Valletta J. S., Zhou J., Long J. B., Mobley W. C. p140trk mRNA marks NGF-responsive forebrain neurons: evidence that trk gene expression is induced by NGF. Neuron. 1992 Sep;9(3):465–478. doi: 10.1016/0896-6273(92)90184-f. [DOI] [PubMed] [Google Scholar]
  19. Hutton L. A., deVellis J., Perez-Polo J. R. Expression of p75NGFR TrkA, and TrkB mRNA in rat C6 glioma and type I astrocyte cultures. J Neurosci Res. 1992 Jul;32(3):375–383. doi: 10.1002/jnr.490320309. [DOI] [PubMed] [Google Scholar]
  20. Ibáez C. F., Ebendal T., Barbany G., Murray-Rust J., Blundell T. L., Persson H. Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by binding to the trk gene product. Cell. 1992 Apr 17;69(2):329–341. doi: 10.1016/0092-8674(92)90413-7. [DOI] [PubMed] [Google Scholar]
  21. Jing S., Tapley P., Barbacid M. Nerve growth factor mediates signal transduction through trk homodimer receptors. Neuron. 1992 Dec;9(6):1067–1079. doi: 10.1016/0896-6273(92)90066-m. [DOI] [PubMed] [Google Scholar]
  22. Kaplan D. R., Hempstead B. L., Martin-Zanca D., Chao M. V., Parada L. F. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science. 1991 Apr 26;252(5005):554–558. doi: 10.1126/science.1850549. [DOI] [PubMed] [Google Scholar]
  23. Kaplan D. R., Martin-Zanca D., Parada L. F. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature. 1991 Mar 14;350(6314):158–160. doi: 10.1038/350158a0. [DOI] [PubMed] [Google Scholar]
  24. Kaye J., Porcelli S., Tite J., Jones B., Janeway C. A., Jr Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J Exp Med. 1983 Sep 1;158(3):836–856. doi: 10.1084/jem.158.3.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Keller R., Keist R., Erb P., Aebischer T., De Libero G., Balzer M., Groscurth P., Keller H. U. Expression of cellular effector functions and production of reactive nitrogen intermediates: a comparative study including T lymphocytes, T-like cells, neutrophil granulocytes, and mononuclear phagocytes. Cell Immunol. 1990 Dec;131(2):398–403. doi: 10.1016/0008-8749(90)90264-r. [DOI] [PubMed] [Google Scholar]
  26. Kimata H., Yoshida A., Ishioka C., Kusunoki T., Hosoi S., Mikawa H. Nerve growth factor specifically induces human IgG4 production. Eur J Immunol. 1991 Jan;21(1):137–141. doi: 10.1002/eji.1830210121. [DOI] [PubMed] [Google Scholar]
  27. Klein R., Jing S. Q., Nanduri V., O'Rourke E., Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189–197. doi: 10.1016/0092-8674(91)90419-y. [DOI] [PubMed] [Google Scholar]
  28. Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987 Sep 4;237(4819):1154–1162. doi: 10.1126/science.3306916. [DOI] [PubMed] [Google Scholar]
  29. Lindholm D., Heumann R., Meyer M., Thoenen H. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature. 1987 Dec 17;330(6149):658–659. doi: 10.1038/330658a0. [DOI] [PubMed] [Google Scholar]
  30. Lion T., Haas O. A. Nonradioactive labeling of probe with digoxigenin by polymerase chain reaction. Anal Biochem. 1990 Aug 1;188(2):335–337. doi: 10.1016/0003-2697(90)90616-h. [DOI] [PubMed] [Google Scholar]
  31. Loeb D. M., Maragos J., Martin-Zanca D., Chao M. V., Parada L. F., Greene L. A. The trk proto-oncogene rescues NGF responsiveness in mutant NGF-nonresponsive PC12 cell lines. Cell. 1991 Sep 6;66(5):961–966. doi: 10.1016/0092-8674(91)90441-z. [DOI] [PubMed] [Google Scholar]
  32. Mallat M., Houlgatte R., Brachet P., Prochiantz A. Lipopolysaccharide-stimulated rat brain macrophages release NGF in vitro. Dev Biol. 1989 May;133(1):309–311. doi: 10.1016/0012-1606(89)90322-9. [DOI] [PubMed] [Google Scholar]
  33. Mallett S., Barclay A. N. A new superfamily of cell surface proteins related to the nerve growth factor receptor. Immunol Today. 1991 Jul;12(7):220–223. doi: 10.1016/0167-5699(91)90033-P. [DOI] [PubMed] [Google Scholar]
  34. Manning P. T., Russell J. H., Simmons B., Johnson E. M., Jr Protection from guanethidine-induced neuronal destruction by nerve growth factor: effect of NGF on immune function. Brain Res. 1985 Aug 5;340(1):61–69. doi: 10.1016/0006-8993(85)90773-5. [DOI] [PubMed] [Google Scholar]
  35. Martin-Zanca D., Oskam R., Mitra G., Copeland T., Barbacid M. Molecular and biochemical characterization of the human trk proto-oncogene. Mol Cell Biol. 1989 Jan;9(1):24–33. doi: 10.1128/mcb.9.1.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Matsuda H., Coughlin M. D., Bienenstock J., Denburg J. A. Nerve growth factor promotes human hemopoietic colony growth and differentiation. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6508–6512. doi: 10.1073/pnas.85.17.6508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mazurek N., Weskamp G., Erne P., Otten U. Nerve growth factor induces mast cell degranulation without changing intracellular calcium levels. FEBS Lett. 1986 Mar 31;198(2):315–320. doi: 10.1016/0014-5793(86)80428-8. [DOI] [PubMed] [Google Scholar]
  38. Meakin S. O., Suter U., Drinkwater C. C., Welcher A. A., Shooter E. M. The rat trk protooncogene product exhibits properties characteristic of the slow nerve growth factor receptor. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2374–2378. doi: 10.1073/pnas.89.6.2374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nebreda A. R., Martin-Zanca D., Kaplan D. R., Parada L. F., Santos E. Induction by NGF of meiotic maturation of Xenopus oocytes expressing the trk proto-oncogene product. Science. 1991 Apr 26;252(5005):558–561. doi: 10.1126/science.1850550. [DOI] [PubMed] [Google Scholar]
  40. Otten U., Ehrhard P., Peck R. Nerve growth factor induces growth and differentiation of human B lymphocytes. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10059–10063. doi: 10.1073/pnas.86.24.10059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pearce F. L., Thompson H. L. Some characteristics of histamine secretion from rat peritoneal mast cells stimulated with nerve growth factor. J Physiol. 1986 Mar;372:379–393. doi: 10.1113/jphysiol.1986.sp016014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Radeke M. J., Misko T. P., Hsu C., Herzenberg L. A., Shooter E. M. Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature. 1987 Feb 12;325(6105):593–597. doi: 10.1038/325593a0. [DOI] [PubMed] [Google Scholar]
  43. Schecterson L. C., Bothwell M. Novel roles for neurotrophins are suggested by BDNF and NT-3 mRNA expression in developing neurons. Neuron. 1992 Sep;9(3):449–463. doi: 10.1016/0896-6273(92)90183-e. [DOI] [PubMed] [Google Scholar]
  44. Scott J., Selby M., Urdea M., Quiroga M., Bell G. I., Rutter W. J. Isolation and nucleotide sequence of a cDNA encoding the precursor of mouse nerve growth factor. Nature. 1983 Apr 7;302(5908):538–540. doi: 10.1038/302538a0. [DOI] [PubMed] [Google Scholar]
  45. Thorpe L. W., Perez-Polo J. R. The influence of nerve growth factor on the in vitro proliferative response of rat spleen lymphocytes. J Neurosci Res. 1987;18(1):134–139. doi: 10.1002/jnr.490180120. [DOI] [PubMed] [Google Scholar]
  46. Weskamp G., Otten U. An enzyme-linked immunoassay for nerve growth factor (NGF): a tool for studying regulatory mechanisms involved in NGF production in brain and in peripheral tissues. J Neurochem. 1987 Jun;48(6):1779–1786. doi: 10.1111/j.1471-4159.1987.tb05736.x. [DOI] [PubMed] [Google Scholar]
  47. Weskamp G., Reichardt L. F. Evidence that biological activity of NGF is mediated through a novel subclass of high affinity receptors. Neuron. 1991 Apr;6(4):649–663. doi: 10.1016/0896-6273(91)90067-a. [DOI] [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