Transmembrane Signals in the Activation of T Lymphocytes

  • John W. Hadden
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 213)


The induction of T lymphocyte proliferation is thought to involve cell-cell interaction and molecular communications (1). The nature of the intercellular communication on a cell-cell contact basis is not understood; what evidence is available points to important molecular communications. It is generally accepted that T cells are triggered to proliferate by two signals (Fig. 1). The mitogen in the relative but not complete absence of accessory cells can induce T cells to enter a G1 phase of the cell cycle from a resting G0 or “restricted” G1 phase of the cell cycle. This first stage of activation is associated with cellular enlargement or blastogenesis and both protein and RNA synthesis. The lymphocyte does not enter DNA synthesis (S phase) unless a second signal is presented. This second process is thought to be initiated by mitogen interaction directly or indirectly with adherent accessory cells, (i.e., monocytes/macrophages) which results in the production of interleukin 1 (IL-1). The IL-1 thus acts on T lymphocytes to induce the production on interleukin 2 (IL-2), and the appearance of cell surface receptors for IL-2. Little is known of the metabolic events associated with IL-1 and IL-2 action. T cells triggered by mitogen to enter the cell cycle transit aG1-S boundary as a result of the second signal and complete the cycle. The subsequent divisions do not require re-exposure to the mitogen but do require the presence of IL-2. The majority of the studies to date have concentrated on early events following mitogen addition to peripheral blood lymphocytes with the assumptions that the events occur in T cells and are contributory to the replication process.


Arachidonic Acid Calcium Influx Guanylate Cyclase Lymphocyte Activation Arachidonic Acid Release 
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  1. 1.
    J. W. Hadden, and R. G. Coffey. Early biochemical events in T lymphocyte activation by mitogens. In Immunopharmacology I, J.W. Hadden & A. Szentivanyi, eds. Pergamon Press, (1986), in press.Google Scholar
  2. 2.
    M. F. Greaves, and S. Bauminger. Activation of T and B lymphocytes by insoluble phytomitogens. Nature New Biol. 235:67–70, (1972).Google Scholar
  3. 3.
    D. A. McClain, and G. M. Edelman. Analysis of the stimulation-inhibition paradox exhibited by lymphocytes. J. Exp. Med. 144:1494–1508, (1976).CrossRefGoogle Scholar
  4. 4.
    J. W. Hadden, E. M. Hadden, J. R. Sadlik, and R. G. Coffey. Effects of concanavalin a and a succinylated derivative on lymphocyte proliferation and cyclic nucleotide levels. Proc. Natl. Acad. Sci. 73:1717–1721, (1976).ADSCrossRefGoogle Scholar
  5. 5.
    R. H. Micheli. Inositol phospholipids and cell surface receptor function. Biochem. Biophvs. Acta. 415:81–147, (1975).CrossRefGoogle Scholar
  6. 6.
    M. J. Berridge. Inositol triphosphate and diacylglycerol as second messengers. Biochem. J. 220:345–360. (1984).Google Scholar
  7. 7.
    R. G. Coffey, and J. W. Hadden. Calcium and guanylate cyclase in lymphocyte activation. In Advances in Immunopharmacology 2, L. Chedid, J.W. Hadden, & A. Willoughby, eds. Pergamon Press, Oxford, (1983) pp 87–94.Google Scholar
  8. 8.
    J. W. Hadden, E. M. Hadden, and R. G. Coffey. Membrane events and guanylate cyclase in mitogen induced lymphocyte activation in leukotrienes. In Prostaglandins, Leukotrienes, & Lipoxins, J.M. Bailey, ed. Plenum Press, New York, (1985) pp 475–486.CrossRefGoogle Scholar
  9. 9.
    D. Y. Hui, and J. A. K. Harmony. Phosphatidylinositol turnover in mitogen-activated lymphocytes. Biochem. J. 192:91–98. (1980).Google Scholar
  10. 10.
    C. W. Parker, W. F. Stenson, M. G. Huber, and J. P. Kelly. Formation of thromboxane B2 and hydroxy arachidonic acids in purified human lymphocytes in the presence and absence of PHA. J. Immunol. 122:1572–1577, (1979).Google Scholar
  11. 11.
    Y. Nishizuka. The role of protein kinase C in cell surface transduction and tumor promotion. Nature 308:693–698, (1984).ADSCrossRefGoogle Scholar
  12. 12.
    Y. Ogawa, Y. Takai, Y. Kawahara, S. Kimura, and Y. Nishizuka. A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes. I. Characterization of a calcium-activated phospholipid-dependent protein kinase. J. Immunol. 127:1369–1374, (1981).Google Scholar
  13. 13.
    Y. Ku, A. Kishimoto, Y. Takai, Y. Ogawa, S. Kimure, and Y. Nishizuka. A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes. II. Possible relation to phosphatidylinositol turnover induced by mitogens. J. Immunol. 127:1375–1379, (1981).Google Scholar
  14. 14.
    F. Hirata, S. Toyoshima, J. Axelrod, and M. F. Waxdal. Phospholipid methylation: A biochemical signal modulating lymphocyte mitogenesis. Proc. Natl. Acad. Sci. 77:862–865, (1980).ADSCrossRefGoogle Scholar
  15. 15.
    J. P. Moore, G. A. Smith, T. R. Hesketh, and J. C. Metcalfe. Early increases in phospholipid methylation are not necessary for the mitogenic stimulation of lymphocytes. J. Biol. Chem. 257:8183–8189, (1982).Google Scholar
  16. 16.
    R. F. Ashman. The influence of cell interactions on early biochemical activation events in human mononuclear cells. Prog. Immunol. 5:339–348, (1984).Google Scholar
  17. 17.
    C. W. Parker, J. P. Kelly, S. F. Falkenhein, and M. G. Huber. Release of arachidonic acid from human lymphocytes in response to mitogenic lectins. J. Exp. Med. 149:1487–1503, (1979).CrossRefGoogle Scholar
  18. 18.
    J. Trotter and E. Ferber. CoA-dependent clevage of arachidonic acid from phosphatidylcholine and transfer to phosphatidylethanolamine in homogenates of murine thymocytes. FEBS Letters 128:237–241, (1981).CrossRefGoogle Scholar
  19. 19.
    K. Resch, M. Brennecke, M. Goppelt, V. Kaever, and M. Szamel. The role of phospholipids in the signal transmission of activated lymphocytes. Prog. Immunol. V:349–360, (1984).Google Scholar
  20. 20.
    E. J. Goetzl. Selective feed-back inhibition of the 5-lipoxygenation of arachidonic acid in human T-lymphocytes. Biochem. Biophvs. Res. Commun. 101:344–350, (1981).CrossRefGoogle Scholar
  21. 21.
    M. E. Goldyne. The generation of 5-lipoxygenase-derived arachidonic acid metabolites among human lymphocytes and monocytes. Prostaglandins and Leukotrienes ’84 — Abstracts of the Fourth Int. Washington Spring Symposium, (1984).Google Scholar
  22. 22.
    J. M. Bailey, R. W. Bryant, E. C. Low, M. B. Pupillo, and J. Y. Vanderhoek. Role of lipoxygenases in regulation of PHA and phorbol ester-induced mitogensis. Adv. Prostaglandins Thromboxanes Leukotrienes Res. 9:341–353, (1982).Google Scholar
  23. 23.
    R. G. Coffey and J. W. Hadden. Stimulation of lymphocyte guanylate cyclase by HETEs. In Prostaglandins, Leudotrienes, and Lipoxins, J. M. Bailey, ed. Plenum Press, New York (1985) pp 501–509.CrossRefGoogle Scholar
  24. 24.
    N. Gualde, D. Atluru, and J. Goodwin. Effect of lipoxygenase metabolites of arachidonic acid on proliferation of human T cells and T cell subsets. J. Immunol. 134:1125–1128, (1985).Google Scholar
  25. 25.
    G. B. Segel, M. M. Hollander, B. R. Gordon, M. R. Klemperer, and M. A. Lichtman. A rapid phytohemagglutinin induced alteration in lymphocyte potassium permeability. J. Cell Physiol. 86:327–335, (1975).CrossRefGoogle Scholar
  26. 26.
    K. G. Chandy, T. E. DeCoursey, M. D. Cahalan, C. McLaugulin, and S. Gupta. Voltage-gated potassium channels are required for human T lymphocyte activation. J. Exp. Med. 160:369–385, (1984).CrossRefGoogle Scholar
  27. 27.
    D. F. Gerson, H. Kiefer, and W. Eufe. Intracellular pH of mitogen-stimulated lymphocytes. Science 216:1009–1010, (1982).ADSCrossRefGoogle Scholar
  28. 28.
    M. F. Berridge. The interaction of cyclic nucleotides and calcium in the control of cellular activity. Adv. Cyclic Nucleotide Res. 6:1–98, (1975).Google Scholar
  29. 29.
    D. A. Hume and M. F. Wiedemann. Intracellular second messengers in mitogenic lymphocyte transformation. Research Monography. Immunology 2:183–225, (1980).Google Scholar
  30. 30.
    R. Hesketh. Cation fluxes and lymphocyte transformation. In The Molecular Basis of Immune Cell Function, J. Gordin Kaplin, ed. Elservier/North-Holland Biomedical Press, Amsterdam (1978) pp 39–56.Google Scholar
  31. 31.
    J. C. Metcalfe, T. Pozzan, G. A. Smith, and T. R. Hesketh. A calcium hypothesis for control of cell growth. Biochem. Soc. Svmp. 45:1–26, (1980).Google Scholar
  32. 32.
    W. C. Greene, C. M. Parker, and C. W. Parker. Calcium and lymphocyte activation. Cell Immunol. 25:74–89. (1976).CrossRefGoogle Scholar
  33. 33.
    T. R. Hesketh, G. A. Smith, M. D. Housley, G. B. Warren, and J. C. Metcalf. Is an early calcium flux necessary to stimulate lymphocytes? Nature 267:490–494, (1977).ADSCrossRefGoogle Scholar
  34. 34.
    M. H. Freedman, N. R. Khan, B. J. Frew-Marshall, C. G. Cupples, and B. Mely-Goubert. Early biochemical events in lymphocyte activation. Cell Immunol. 58:134–146, (1981).CrossRefGoogle Scholar
  35. 35.
    R. Y. Tsien, T. Pozzan, and T. J. Rink. T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes. Nature 295:68–70, (1982).ADSCrossRefGoogle Scholar
  36. 36.
    C. W. Parker, T. F. Sullivan, and J. H. Wedner. Cyclic AMP and the immune response. Adv. Cyclic Nucleotide Res. 4:1–80, (1974).Google Scholar
  37. 37.
    H. J. Wedner and C. W. Parker. Lymphocyte Activation. Prog. Allergy 20:195–300, (1976).CrossRefGoogle Scholar
  38. 38.
    T. B. Strom, A. P. Lundin, and C. B. Carpenter. The role of cyclic nucleotides in lymphocyte activation and function. Prog. Clin. Immunol. 3:115–153, (1977).Google Scholar
  39. 39.
    J. W. Hadden and R. G. Coffey. Cyclic nucleotides in mitogen induced lymphocyte proliferation. Immunology Today 3:299–304. (1982).CrossRefGoogle Scholar
  40. 40.
    J. W. Smith, A. L. Steiner, W. M. Newberry, and C. W. Parker. Cyclic adenosine 3′,5′-monosphosphate in human lymphocytes. Alterations after phytohemagglutinin stimulation. J. Clin. Invest. 50:432–441, (1971).CrossRefGoogle Scholar
  41. 41.
    W. C. Greene, C. M. Parker, and C. W. Parker. Opposing effects of mitogenic and nonmitogenic lectins on lymphocyte activation. J. Biol. Chem. 251:4017–4025, (1976).Google Scholar
  42. 42.
    J. W. Hadden, E. M. Hadden, M. K. Haddox, and N. D. Goldberg. Guanosine 3′,5′-cyclic monophosphate: A possible intracellular mediator of mitogen influences in lymphocytes. Proc. Natl. Acad. Sci. 69:3024–3027, (1972).ADSCrossRefGoogle Scholar
  43. 43.
    J. Ohara and T. Watanabe. Microinjection of macromolecules into normal murine lymphocytes by cell fusion technique. I. Quantitative microinjection of antibodies into normal splenic lymphocytes. J. Immunol. 128:1090–1096, (1982).Google Scholar
  44. 44.
    F. E. Bloom, H. Wedner, and C. W. Parker. The use of antibodies to study cell structure and metabolism. Pharmacol. Rev. 25:343–358, (1973).Google Scholar
  45. 45.
    C. V. Byus, G. R. Klimpel, D. O. Lucas, and D. H. Russell. Ornithine decarboxylase induction in mitogen-stimulated lymphocytes is related to the specific activation of type I adenosine cyclic 3′,5′-monophosphate-dependent protein kinase. Mol. Pharmacol. 14:431–441, (1978).Google Scholar
  46. 46.
    M. T. Largen and B. Votta. Immunocytochemical evidence for 3′,5′-cGMP and 3′,5′-cGMP-dependent protein kinase involvement in lymphocyte proliferation. J. Cyclic Nucl. Prot. Phosphor. Res. 9:231–244, (1983).Google Scholar
  47. 47.
    M. I. Mednieks and R. A. Jungmann. Selective expression of type I and type II cyclic AMP-dependent protein kinases in subcellular fractions of concanavalin A-stimulated rat thymocytes. Arch. Biochem. Biophvs. 213:127–138, (1982).CrossRefGoogle Scholar
  48. 48.
    N. D. Goldberg, G. Graff, M. K. Haddox, J. H. Stephenson, D. B. Glass, and M. E. Moser. Redox modulation of splenic cell soluble guanylate cyclase activity: Activation by hydrophilic and hydrophobic oxidants represented by ascorbic and dehydroascorbic acids, fatty acid, hydroperoxides and prostagliadin endoperoxides. Adv. Cyclic Nucleotide Res. 9:101–130, (1978).Google Scholar
  49. 49.
    R. Ananthakrishnan, R. G. Coffey, and J. W. Hadden. Cyclic GMP and calcium in lymphocyte activation by phytohemagglutinin. Human Lymphocyte Differentiation 1:183–196, (1981).Google Scholar
  50. 50.
    L. D. Johnson and J. W. Hadden. Modification of human DNA-dependent RNa of lymphocyte nuclear acidic polymerase by cyclic GMP. Nucleic Acid Res. 4:4007–4014, (1977).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • John W. Hadden
    • 1
  1. 1.Program of ImmunopharmacologyUniversity of South Florida Medical CollegeTampaUSA

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