Characterization of Signals Leading to Clonal Expansion or to Cell Death During Lymphocyte B Cell Activation

  • L. Bosca
  • C. Stauber
  • S. Hortelano
  • E. Baixeras
  • C. Martinez-A.
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 200)


The immune system is endowed with a multitude of different mechanisms to eliminate, paralyze or neutralize T and B lymphocytes expressing self-reactive antigen receptors that might endanger the individual’s life. The ability of both types of lymphocytes to recognize and react to different stimuli is a learning process that occurs during lymphocyte differentiation, and the mechanisms implicated in self-tolerance intervene at determined control points following developmental criteria. B and T lymphocyte differentiation from committed precursor cells into antibody-secreting plasma cells or effector T cells proceeds through multiple steps that are defined by changes in the expression pattern of lineage-specific genes (Moller 1994).


Nitric Oxide Nitric Oxide Clonal Expansion European Molecular Biology Organization Commit Precursor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albina J E, Abate JA, Henry W-J (1991) Nitric oxide production is required for murine resident peritoneal macrophages to supress mitogen-stimulated T cell proliferation. J Immunol 147: 144–148PubMedGoogle Scholar
  2. Albina JE, Cui S, Mateo RB, Reichner JS (1993) Nitric-oxide mediated apoptosis in murine peritoneal macrophages. J Immunol 150: 5080–5085PubMedGoogle Scholar
  3. Baixeras E, Kroemer G, Cuende E, Márquez C, Boscá L, Alés Martínez JE, Martinez-AC (1993) Signal transduction pathways involved in B cell induction. Immunol Rev 132: 5–47PubMedCrossRefGoogle Scholar
  4. Bierer BE, Hahn WC (1993) T cell adhesion, avidity regulation and signaling: a molecular analysis of CD2. Semin Immunol 5: 249–261PubMedCrossRefGoogle Scholar
  5. Billiar TR, Curran RD, Stuehr DJ, Stadler J, Simmons RL, Murray SR (1990) Inducible cytosolic enzyme activity for the production of nitrogen oxides from L-arginine in hepatocytes. Biochem Biophys Res Commun 168: 1034–1040PubMedCrossRefGoogle Scholar
  6. Bogdan C, Vodovotz Y, Paik J, Xie Q.-W, Nathan C (1993) Traces of bacterial lipopolysaccharide suppress IFN-induced nitric oxide synthase gene expression in primary mouse macrophages. J Immunol 151: 301–309PubMedGoogle Scholar
  7. Bredt DS, Snyder SH (1989) Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the corebellum. Proc Natl Acad Sci USA 86: 9030–9033PubMedCrossRefGoogle Scholar
  8. Bredt DS, Snyder SH (1992) Nitric oxide, a novel nouronal messenger. Neuron 8: 3–11PubMedCrossRefGoogle Scholar
  9. Bredt DS, Hwang PM, Snyder SH (1990) Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347: 768–770PubMedCrossRefGoogle Scholar
  10. Brune B, Lapetina EG (1989) Activation of a cytosotic ADP-ribosyltransferase by nitric oxide-generating agents. J Biol Chem 264: 8455–8458PubMedGoogle Scholar
  11. Clark EA, Lane PJL (1991) Regulation of human B cell activation and adhesion. Annu Rev Immunol 9: 97–127PubMedCrossRefGoogle Scholar
  12. Clark EA, Ledbetter JA (1994) How B and T cells talk to each other. Nature 367: 425–428PubMedCrossRefGoogle Scholar
  13. Danielian S, Fagard R, Alcover A, Acuto O, Fischer S (1991) The tyrosine kinase activity of p56lck is increased in human T cells activated via CD2. Eur J Immunol 21: 1967–1970PubMedCrossRefGoogle Scholar
  14. Danielian S, Alcover A, Polissard L, Stefanescu M, Acuto O, Fisher S, Fagard R (1993) Both T cell receptor (TCR)-CD3 complex and CD2 increase the tyrosine kinase activity of p56lck. CD2 can mediate TCR-CD3 independent and CD45-dependent activation of p56lck. Eur J Immunol 22: 2915–2921CrossRefGoogle Scholar
  15. Ding AH, Nathan CF, Graycar J, Derynck R, Stueh DJ, Srimai S (1990) Macrophage deactivating factor and transforming growth factors 1, 2 and 3 inhibit induction on macrophage nitrogen oxide synthesis by IFN. J Immunol 145: 940–944PubMedGoogle Scholar
  16. Dong Z, Qi X, Xie K, Fidler IJ (1993) Protein tyrosine kinase inhibitors decrease induction of nitric Oxoid synthase activity in lipopolysaccharide-responsive and lipopolysaccharide-nonresponsive murine macrophages. J Immunol 151: 2717–2724PubMedGoogle Scholar
  17. Drapier JC, Hibbs JB Jr (1986) Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible. J Clin Invest 78: 790–795PubMedCrossRefGoogle Scholar
  18. Fernandez-Sarabia MJ, Bischoff JR (1993) Bcl-2 associates with the ras-related protein R-ras p23. Nature 366: 274–275PubMedCrossRefGoogle Scholar
  19. Furchgott RF (1988) Studies on relaxation of Rabbit aorta by sodium nitrite: the basis for the proposal that the acid activatable inhibitory factor from retractor penis is inorganic nitrite and the endothelium-derived relaxing factor is nitric oxide. In: Vanhoutte PM (ed) Mechanism of vasodilation. Raven, New York, p401Google Scholar
  20. Garg UC, Hassid AS (1989) Nitric oxide-generating vasodilators and B-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83: 1774–1777PubMedCrossRefGoogle Scholar
  21. Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR (1993a) Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci USA 90: 3491–3495PubMedCrossRefGoogle Scholar
  22. Geller DA, Nussler AK, Di Silvio M, Lowenstein CJ, Shapiro RA, Wang SC, Simmons RL, Billiar TR (1993b) Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci USA 90: 522–526PubMedCrossRefGoogle Scholar
  23. Genaro AM and Boscá L (1993) Early signals in alloantigen induced B cell proliferation. J Immunol 151: 1832–1843PubMedGoogle Scholar
  24. Genaro AM, Gonzálo JA, Boscá L, Martínez- A. C (1994) CD2 occupancy prevents apoptosis in murine B lymphocytes by upregulating Bcl-2 expression. Eur J Immunol 24: 2515–2521PubMedCrossRefGoogle Scholar
  25. Golay J, Cusmano G, Introma M (1992) Independent regulation of c-myc, b-myb and c-myb gene expression by inducers and inhibitors of proliferation in human B lymphocytes. J Immunol 149: 300–308PubMedGoogle Scholar
  26. Granger DL, Taintor RR, Cook JL, Hibbs JB (1980) Injury in neoplastic cells by murine macrophages leads to inhibition of mitochondrial respiration. J Clin Invest 65: 357PubMedCrossRefGoogle Scholar
  27. Hauschildt S, Luckhoff A, Mulsch A, Kohler J, Bessler W, Busse RS (1990) Induction and activity of NO syntase in bone marrow derived macrophages are independent of Ca2+. Biochem J 270: 351PubMedGoogle Scholar
  28. Hoffman RA, Langrehr JM, Billiar TR, Curran RD, Simmons RL (1990) Alloantigen-induced activation of rat splenocytes is regulated by oxidative metabolism of L-arginiene. J Immunol 145: 2220–2226PubMedGoogle Scholar
  29. Ischiropoulos H, Zhu L, Beckman JS (1992) Peroxynitrite formation from macrophage-derived nitric oxide. Arch Biochem Biophys 298: 446–451PubMedCrossRefGoogle Scholar
  30. Jenkins MK, Johnson JC (1993) Molecules involved in T-cell costimulation. Curr Opin Immunol 5: 361–367PubMedCrossRefGoogle Scholar
  31. Jonathan S, Reichner JS, Mateo RB, Albina JE (1994) Activated murine macrophages induce apoptosis in tumor cells through nitric oxide-dependent or-independent mechanisms. Cancer Res 54: 2462–2467Google Scholar
  32. Kelsoe G, Zheng B (1993) Sites of B-cell activation in vivo. Curr Opin Biol 5: 418–422Google Scholar
  33. Knowles RG, Moncada S (1992) Nitric oxide as a signal in blood vessels. Trends Biochem Sci 17: 399–402PubMedCrossRefGoogle Scholar
  34. Knowles RG, Palacios M, Palmer RMJ, Moncada S (1989) Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci USA 86: 5159–5162PubMedCrossRefGoogle Scholar
  35. Krammer P, Behrman I, Daniel P, Dhein J, Debatin K-M (1994) Regulation of apoptosis in the immune system. Curr Opin Immunol 6: 279–289PubMedCrossRefGoogle Scholar
  36. Kroemer G, Martinez- AC (1994) Pharmacological inhibition of programmed cell death. Immunol Today 15: 235–242PubMedCrossRefGoogle Scholar
  37. Langrehr JM, Murase N, Markus PM, Cai X, Neuhaus P, Schraut W, Simmons RL, Hoffman RA (1992) Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat. J Clin Invest 90: 679–683PubMedCrossRefGoogle Scholar
  38. Lepoivre M, Chenais B, Yapo A, Lemaire G, Thelander L, Tenu J-P (1990) Alterations of ribonucleotide reductase activity following induction of the nitrite-generating pathway in adenocarcinoma cells. J Biol Chem 265: 14143–14149PubMedGoogle Scholar
  39. Liew FY, Li Y, Severn A, Millott S, Schmidt J, Slater M, Moneada S (1991) A possible novel pathway of regulation by murine T helper type-2 (Th2) cells of a Th1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages. Eur J Pharmacol 21: 3009–3014Google Scholar
  40. Lipton SA, Choi YB, Pan ZH, Lei SZ, Chen HS, Sucher NJ, Loscalzo J, Singel DJ, Stamler JS (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide an related nitrosocompounds. Nature 364: 626–632PubMedCrossRefGoogle Scholar
  41. Loffert D, Schaal S, Erlich A, Hardy RR, Zon Y-R, Muller W, Rajewsky K (1994) Early B-cell development in the mouse: insights from mutations introduced by gene targeting. Immunol Rev 137: 135–172PubMedCrossRefGoogle Scholar
  42. Lowenstein CJ, Snyder SH (1992) Nitric oxide, a novel biological messenger. Cell 70: 705–707PubMedCrossRefGoogle Scholar
  43. Lowenstein CJ, Dinerman JL, Snyder SH (1994) Nitric Oxide: a physiologic Messenger. Ann Intern Med 120: 227–237PubMedGoogle Scholar
  44. Lyons CR, Orloff GJ, Cunningham JM (1992) Molecular cloning and functional expression of a inducible NOS from a murine macrophage cell line. J Biol Chem 267: 6370–6374PubMedGoogle Scholar
  45. Marletta MA, Yoon PS, Iyengar R, Leaf CD, Wishnok JS (1988) Macrophage oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochemistry 27: 8706–8711PubMedCrossRefGoogle Scholar
  46. Marquez C, Martínez-AC, Kroemer G, Boscá L (1992) Protein kinase C isoenzymes display differential affinity for phorbol esters. Analysis of phorbol ester receptors in B cell differentiation. J Immunol 149: 2560–2568PubMedGoogle Scholar
  47. McCartney F, Allen N, Mizel DE, Albina JE, Xie Q-W, Nathan CF, Wahl SM (1993) Supression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med 178: 749–754CrossRefGoogle Scholar
  48. Merino R, Ding L, Veis DJ, Korsmeyer SJ, Nuñez G (1994) Developmental regulation of the bcl-2 protein and susceptibility to cell death in B lymphocytes. EMBO J 23: 683–691Google Scholar
  49. Moingeon P, Chang H, Sayre PH, Clayton LK, Alcover A, Gardner P, Reinherz EL (1989a) The structural biology of CD2. Immunol Rev 111: 111–114PubMedCrossRefGoogle Scholar
  50. Moingeon P, Chang HC, Wallner BP, Stebbins C, Frey AZ, Reinherz EL (1989b) CD2 mediated adhesion facilitates T lymphocyte antigen recognition function. Nature 339: 312PubMedCrossRefGoogle Scholar
  51. Möller G (1992) Cytokines in infectious disease. Immunol Rev 126: 5–178CrossRefGoogle Scholar
  52. Möller G (ed) (1994) B-cell differentiation. Immunol Rev 137: 5–229Google Scholar
  53. Moneada S (1992) The L-arginine: nitric oxide pathway. Acta Physiol Scand 145: 201–227CrossRefGoogle Scholar
  54. Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329: 2002–2012PubMedCrossRefGoogle Scholar
  55. Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43: 109–143PubMedGoogle Scholar
  56. Muraguchi A, Kawamura N, Hon A, Horii Y, Ichigi Y, Kimoto M, Kishimoto T (1992) Expression of the CD2 molecule on human B lymphoid progenitors. Int Immunol 4: 841–849PubMedCrossRefGoogle Scholar
  57. Nathan C (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J 6: 3051–3064PubMedGoogle Scholar
  58. Nuñez G, London L, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ (1990a) Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hematopoietic cell lines. J Immunol 144: 3602–3610PubMedGoogle Scholar
  59. Nuñez G, London, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ (1990b) Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hematopoietic cell lines. J Immunol 144: 3602–3610PubMedGoogle Scholar
  60. Palmer RMJ (1993) The discovery of nitric oxide in the vessel wall. Arch Surg 128: 396–401PubMedGoogle Scholar
  61. Palmer RMJ, Ferridge AG, Moneada S (1987) Nitric oxide accounts for the biological activity of endothelium-derived relaxing factor. Nature 327: 524–526PubMedCrossRefGoogle Scholar
  62. Parker DC (1993) T cell dependent B cell activation. Annu Rev Immunol 11: 331–360PubMedCrossRefGoogle Scholar
  63. Punnonen J, de-Vries JE (1993) Characterization of a novel CD2+ human thymic B cell subset. J Immunol 151: 100–110PubMedGoogle Scholar
  64. Rincon M, Tugores A, Landazuri MA, Lopez-Botet M (1993) Costimulation of cAMP and protein kinase C pathways inhibits the CD3-dependent T cell activation and leads to a persistent expression of the AP-1 transcription factor. Cell Immunol 149: 343–356PubMedCrossRefGoogle Scholar
  65. Sen J, Rosenberg N, Burakoff S (1990) Expression and ontogeny of CD2 on murine B cells. J Immunol 144: 2925–2930PubMedGoogle Scholar
  66. Stuehr DJ, Marietta MA (1985) Mammaliam nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc Natl Acad Sci USA 82: 7738–7742PubMedCrossRefGoogle Scholar
  67. Stuehr DJ, Cho JJ, Kwon NS, Nathan C (1991) Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: a FAD- and FMN containing flavoprotein. Proc Natl Acad Sci USA 88: 7773–7777PubMedCrossRefGoogle Scholar
  68. Tson K, Snyder GL, Greengard P (1993) Nitric oxide/cAMP pathway stimulates phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, in the substantianigra. Proc Natl Acad Sci USA 90: 3462–3465CrossRefGoogle Scholar
  69. Tsubata T, Wu J, Honjo T (1993) B cell apoptosis induced by antigen receptor crosslinking is blocked by a T cell signal through CD40. Nature 364: 645–648PubMedCrossRefGoogle Scholar
  70. Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S (1992) Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314–317PubMedCrossRefGoogle Scholar
  71. Watson ML, Rao JK, Gilkeson GS, Ruiz P, Eicher EM, Pisetsky DS, Matsuzawa A, Rochell JM, Seldin MF (1992) Genetic analysis of MRL/Ipr mice: relationship of the Fas apoptosis gene to didease manifestation and renal modifying loci. J Exp Med 176: 1645–1656PubMedCrossRefGoogle Scholar
  72. Weinberg JB, Granger DL, Pisetsky DS, Seldin MF, Misukonis MA, Mason SN, Rippen AM, Ruiz P, Wood ER, Gilkeson GS (1994) The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: Increased nitric oxide production and nitric oxide syntase expression in MRL Ipr/Ipr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered N monomethyl-L-arginine. J Exp Med 179: 651–660PubMedCrossRefGoogle Scholar
  73. Xie Q-W, Whisnant R, Nathan C (1993) Promoter of the mouse gene encoding calcium independent nitric oxide synthase confers inducibility by interferon and bacterial lipopolysaccharide. J Exp Med 177:1779–1784PubMedCrossRefGoogle Scholar
  74. Yagita H, Nakamura T, Karasuyama H, Okumura K (1989) Monoclonal antibodies specific for murine CD2 reveal its presence on B as well as T cells. Proc Natl Acad Sci USA 86: 645–649PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • L. Bosca
    • 1
  • C. Stauber
    • 2
  • S. Hortelano
    • 1
  • E. Baixeras
    • 2
  • C. Martinez-A.
    • 2
  1. 1.Instituto de Bioquimica, CSICUniversidad ComplutenseMadridSpain
  2. 2.Centro Nacional de Biolecnologia CSICUniversidad AutonomaMadridSpain

Personalised recommendations