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Mechanisms of Lymphocyte Activation and Immune Regulation V pp 9–22Cite as

Mechanism of B Cell Antigen Receptor Function: Transmembrane Signaling and Triggering of Apoptosis

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 365))

Abstract

The B cell antigen receptor (BCR) plays a key role in regulating B cell development, activation, and inactivation1. The transmembrane form of μ is required for proper B cell development2, as is the surrogate light chain encoded by the λ5 gene3. Once the immunoglobulin (Ig) genes have been rearranged properly, the B cell precursor expresses the conventional form of the BCR. If this immature B cell contacts antigen before leaving the bone marrow, it continues to rearrange the Ig light chain genes4,5. This response, referred to as receptor editing, is presumably an effort to change antigen specificity away from what would usually be self-reactivity. If unsuccessful in altering its antigen specificity, this auto-reactive immature B cell is inactivated either by cell death6–8 or clonal anergy9.

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References

  1. A.L. DeFranco, Structure and function of the B cell antigen receptor, Ann. Rev. Cell Biol. 9: 377 (1993).

    Article  PubMed  CAS  Google Scholar 

  2. D. Kitamura, J. Roes, R. Kuhn, and K. Rajewsky, A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain, Nature 350:423 (1991).

    Article  PubMed  CAS  Google Scholar 

  3. D. Kitamura, A. Kudo, S. Schaal, W. Muller, F. Melchers, and K. Rajewsky, A critical role of λ5 protein in B cell development., Cell 69: 823 (1992).

    Article  PubMed  CAS  Google Scholar 

  4. D. Gay, T. Saunders, S. Camper, and M. Weigert, Receptor editing: an approach by autoreactive B cells to escape tolerance, J. Exp. Med. 177: 999 (1993).

    Article  PubMed  CAS  Google Scholar 

  5. S.L. Tiegs, D.M. Russell, and D. Nemazee, Receptor editing in self-reactive bone marrow B cells, J. Exp. Med. 177: 1009 (1993).

    Article  PubMed  CAS  Google Scholar 

  6. D.M. Russell, Z. Dembic, G. Morahan, J.F. Miller, K. Burki, and D.A. Nemazee, Peripheral deletion of self-reactive B cells, Nature 354: 308 (1991).

    Article  PubMed  CAS  Google Scholar 

  7. S.B. Hartley, J. Crosbie, R. Brink, A.B. Kantor, A. Basten, and C.C. Goodnow, Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens, Nature 353: 765 (1991).

    Article  PubMed  CAS  Google Scholar 

  8. M. Murakami, T. Tsubata, M. Okamoto, A. Shimizu, S. Kumagai, H. Imura, and T. Honjo, Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice, Nature 357: 77 (1992).

    Article  PubMed  CAS  Google Scholar 

  9. C.C. Goodnow, J. Crosbie, S. Adelstein, T.B. Lavoie, S J. Smith-Gill, R. Brink, H. Pritchard-Briscoe, J.S. Wotherspoon, R.H. Loblay, K. Raphael, R.J. Trent, and A. Basten, Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice, Nature 334:676 (1988).

    Article  PubMed  CAS  Google Scholar 

  10. A.L. DeFranco, Molecular aspects of B-lymphocyte activation, Ann. Rev. Cell Biol. 3: 143 (1987).

    Article  PubMed  CAS  Google Scholar 

  11. Y.-J. Liu, D.E. Joshua, G.T. Williams, C.A. Smith, J. Gordon, and I.C.M. MacLennan, Mechanism of antigen-driven selection in germinal centres, Nature 342: 929 (1989).

    Article  PubMed  CAS  Google Scholar 

  12. M. Reth, Antigen receptors on B lymphocytes, Ann. Rev. Immunol. 10: 97 (1992).

    Article  CAS  Google Scholar 

  13. G.T. Williams, A.R. Venkitaraman, D.J. Gilmore, and M.S. Neuberger, The sequence of the mu transmembrane segment determines the tissue specificity of the transport of immunoglobulin M to the cell surface, J. Exp. Med. 171: 947 (1990).

    Article  PubMed  CAS  Google Scholar 

  14. A.R. Venkitaraman, G.T. Williams, P. Dariavach, and M.S. Neuberger, The B cell antigen receptor of the five immunoglobulin classes, Nature 352: 777 (1991).

    Article  PubMed  CAS  Google Scholar 

  15. L. Matsuuchi, M.R. Gold, A. Travis, R. Grosschedl, A.L. DeFranco, and R.B. Kelly, The membrane IgM-associated proteins MB-1 and Ig-β are sufficient to promote surface expression of a partially functional B-cell antigen receptor in a nonlymphoid cell line, Proc. Natl. Acad. Sci. USA 89: 3404 (1992).

    Article  PubMed  CAS  Google Scholar 

  16. B J. Cherayil, K. MacDonald, G.L. Waneck, and S. Pillai, Surface transport and internalization of the membrane IgM H chain in the absence of the Mb-1 and B29 proteins, J. Immunol. 151: 11 (1993).

    PubMed  CAS  Google Scholar 

  17. T.L. Stevens, J.B. Blum, S.P. Foy, L. Matsuuchi, and A.L. DeFranco, A mutation of the μ transmembrane that disrupts ER retention: effects on association with accessory proteins and signal transduction, J. Immunol. 152: in press (1994).

    Google Scholar 

  18. E. Degen and D.B. Williams, Participation of a novel 88-kD protein in the biogenesis of murine class I histocompatability molecules, J. Cell Biol. 112: 1099 (1991).

    Article  PubMed  CAS  Google Scholar 

  19. F. Hochstenbach, V. David, S. Watkins, and M.B. Brenner, Endoplasmic reticulum resident protein of 90 kilodaltons associates with the T-and B-cell antigen receptors and major histocompatability antigens during their assembly, Proc. Natl. Acad. Sci. USA 89:4734 (1992).

    Article  PubMed  CAS  Google Scholar 

  20. J. Hombach, T. Tsubata, L. Leclercq, H. Stappert, and M. Reth, Molecular components of the B-cell antigen receptor complex of the IgM class, Nature 343: 760 (1990).

    Article  PubMed  CAS  Google Scholar 

  21. J.H. Blum, T.L. Stevens, and A.L. DeFranco, Role of the μ immunoglobulin heavy chain transmembrane and cytoplasmic domains in B cell antigen receptor expression and signal transduction, J. Biol. Chem. 27238-27247: (1993).

    Google Scholar 

  22. A.C. Shaw, R.N. Mitchell, Y.K. Weaver, J. Campos-Torres, A.K. Abbas, and P. Leder, Mutations of immunoglobulin transmembrane and cytoplasmic domains: Effects on intracellular signaling and antigen presentation, Cell 63: 381 (1990).

    Article  PubMed  CAS  Google Scholar 

  23. R.N. Mitchell, A.C. Shaw, Y.K. Weaver, P. Leder, and A.K. Abbas, Cytoplasmic tail deletion converts membrane immunoglobulin to a phosphatidylinositol-linked form lacking signaling and efficient antigen internalization functions, J. Biol. Chem. 266: 8856 (1991).

    PubMed  CAS  Google Scholar 

  24. M. Sanchez, Z. Misulovin, A.L. Burkhardt, S. Mahajan, T. Costa, R. Franke, J.B. Bolen, and M. Nussenzweig, Signal transduction by immunoglobulin is mediated through Ig-α and Ig-β, J. Exp. Med. 178: 1049 (1993).

    Article  PubMed  CAS  Google Scholar 

  25. W.K. Tsang, J. Mizuguchi, Y. Ishida, C. Watson, T. Chused, J. Inman, D.H. Margulies, and W.E. Paul, Failure of signaling through a chimeric class I-immunoglobulin molecule expressed on the surface of transfected B lymphoma cells and cells of transgenic mice, Cell. Immunol. 143: 80 (1992).

    Article  PubMed  CAS  Google Scholar 

  26. A.L. DeFranco, Tyrosine phosphorylation and the mechanism of signal transduction by the B-lymphocyte antigen receptor, Eur. J. Biochem. 210: 381 (1992).

    Article  PubMed  CAS  Google Scholar 

  27. R.H. Carter, D.J. Park, S.G. Rhee, and D.T. Fearon, Tyrosine phosphorylation of phospholipase C induced by membrane immunoglobulin in B lymphocytes, Proc. Natl. Acad. Sci. USA 88: 2745 (1991).

    Article  PubMed  CAS  Google Scholar 

  28. W.M. Hempel, R.C. Schatzman, and A.L. DeFranco, Tyrosine phosphorylation of phospholipase C γ2 upon crosslinking of membrane Ig on murine B lymphocytes, J. Immunol. 148: 3021 (1992).

    PubMed  CAS  Google Scholar 

  29. K.M. Coggeshall, J.C. McHugh, and A. Altman, Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-72 in B lymphocytes, Proc. Natl. Acad. Sci. USA 90: 5660 (1992).

    Article  Google Scholar 

  30. S.B. Kanner, J.P. Deans, and J.A. Ledbetter, Regulation of CD3-induced phospholipase C-gammal (PLCγl) tyrosine phosphorylation by CD4 and CD45 receptors, Immunology 75: 441 (1992).

    PubMed  CAS  Google Scholar 

  31. CM. Roifman and G. Wang, Phospholipase C-γl and phospholipase C-γ2 are substrates of the B cell antigen receptor associated protein tyrosine kinase, Biochem. Biophys. Res. Commun. 183: 411 (1992).

    Article  PubMed  CAS  Google Scholar 

  32. C.F. Webb, C. Nakai, and P.W. Tucker, Immunoglobulin receptor signalling depends on the carboxyl terminus but not the heavy-chain class, Proc. Natl. Acad. Sci. USA 86: 1977 (1989).

    Article  PubMed  CAS  Google Scholar 

  33. P.M. Dubois, J. Stepinski, J. Urbain, and C.H. Sibley, Role of the transmembrane and cytoplasmic domains of surface IgM in endocytosis and signal transduction, Eur. J. Immunol. 22: 851 (1992).

    Article  PubMed  CAS  Google Scholar 

  34. S.A. Grupp, K. Campbell, R.N. Mitchell, J.C. Cambier, and A.K. Abbas, Signaling-defective mutants of the B lymphocyte antigen receptor fail to associate with Ig-α and Ig-β/γ, J. Biol. Chem. 268: 25776 (1993).

    PubMed  CAS  Google Scholar 

  35. J.C. Cambier, Signal transduction by T-and B-cell antigen receptors: converging structures and concepts, Curr. Opin. Immunol. 4: 257 (1992).

    Article  PubMed  CAS  Google Scholar 

  36. L.E. Samelson and R.D. Klausner, Tyrosine kinases and tyrosine-based activation motifs, J. Biol. Chem. 267: 24913 (1992).

    PubMed  CAS  Google Scholar 

  37. A. Weiss, T cell antigen receptor signal transduction: A tale of tails and cytoplasmic protein-tyrosine kinases, Cell 73: 209 (1993).

    Article  PubMed  CAS  Google Scholar 

  38. B. Irving and A. Weiss, The cytoplasmic domain of the T cell receptor ζ chain is sufficient to couple to receptor-associated signal transduction pathways, Cell 64: 891 (1991).

    Article  PubMed  CAS  Google Scholar 

  39. B.A. Irving, A.C. Chan, and A. Weiss, Functional characterization of a signal transducing motif present in the T cell antigen receptor ζ chain, J. Exp. Med. 177:1093 (1993).

    Article  PubMed  CAS  Google Scholar 

  40. C. Romeo and B. Seed, Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides, Cell 64: 1037 (1991).

    Article  PubMed  CAS  Google Scholar 

  41. C. Romeo, M. Amiot, and B. Seed, Sequence requirements for induction of cytolysis by the T cell antigen/Fc receptor ζ chain, Cell 68: 889 (1992).

    Article  PubMed  CAS  Google Scholar 

  42. A.-M.K. Wegener, F. Letourneur, A. Hoeveler, T. Brocker, F. Luton, and B. Malissen, The T cell receptor/CD3 complex is composed of at least two autonomous transduction molecules, Cell 68: 83 (1992).

    Article  PubMed  CAS  Google Scholar 

  43. F. Letourneur and R.D. Klausner, Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3 ε, Science 255: 79 (1992).

    Article  PubMed  CAS  Google Scholar 

  44. K.-M. Kim, G. Alber, P. Weiser, and M. Reth, Differential signaling through the Ig-α and Ig-β components of the B cell antigen receptor, Eur. J. Immunol. 23: 911 (1993).

    Article  PubMed  CAS  Google Scholar 

  45. D.A. Law, V.W.F. Chan, S.K. Datta, and A.L. DeFranco, B-cell antigen receptor motifs have redundant signalling capabilities and bind the tyrosine kinases PTK72, Lyn and Fyn, Curr. Biol. 3: 645 (1993).

    Article  PubMed  CAS  Google Scholar 

  46. W.J. Fantl, J.A. Escobedo, G.A. Martin, C.W. Turck, M. del Rosario, F. McCormick, and L.T. Williams, Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways, Cell 69: 413 (1992).

    Article  PubMed  CAS  Google Scholar 

  47. A. Kazlauskas, A. Kashishian, J.A. Cooper, and M. Valius, GTPase-activating protein and phosphatidylinositol 3-kinase bind to a distinct region of the platelet-derived growth factor receptor β subunit, Mol. Cell. Biol. 12: 2534 (1992).

    PubMed  CAS  Google Scholar 

  48. M. Rozakis-Adcock, J. McGlade, G. Mbamalu, G. Pelicci, R. Daly, W. Li, A. Batzer, S. Thomas, J. Brugge, P.G. Pelicci, J. Schlessinger, and T. Pawson, Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases, Nature 360: 689 (1992).

    Article  PubMed  CAS  Google Scholar 

  49. E.J. Lowenstein, R.J. Daly, A.G. Batzer, W. Li, B. Margolis, R. Lammers, A. Ullrich, E. Skolnik, D. Bar-Sagi, and J. Schlessinger, The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling, Cell 70: 431 (1992).

    Article  PubMed  CAS  Google Scholar 

  50. J.P. Olivier, T. Raabe, M. Henkemeyer, B. Dickson, G. Mbamalu, B. Margolis, J. Schlessinger, E. Hafen, and T. Pawson, A Drosophila SH2-SH3 adapter protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos, Cell 73:179 (1993).

    Article  PubMed  CAS  Google Scholar 

  51. Z. Songyang, S.E. Shoelson, M. Chaudhuri, G. Gish, T. Pawson, W.G. Haser, F. King, T. Roberts, S. Ratnofsky, R.J. Lechleider, B.G. Neel, R.B. Birge, J.E. Fajardo, M.M. Chou, H. Hanafusa, B. Schaffhausen, and L.C. Cantley, SH2 domains recognize specific phosphoprotein sequences, Cell 72: 767 (1993).

    Article  PubMed  CAS  Google Scholar 

  52. J.E. Hutchcroft, M.L. Harrison, and R.L. Geahlen, B lymphocyte activation is accompanied by phosphorylation of a 72-kDa protein-tyrosine kinase, J. Biol. Chem. 266: 14846 (1991).

    PubMed  CAS  Google Scholar 

  53. J.E. Hutchcroft, M.L. Harrison, and R.L. Geahlen, Association of the 72-kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor, J. Biol Chem. 267: 8613 (1992).

    PubMed  CAS  Google Scholar 

  54. W. Kolanus, C. Romeo, and B. Seed, T cell activation by clustered tyrosine kinases, Cell 74: 171 (1993).

    Article  PubMed  CAS  Google Scholar 

  55. J.M. Pesando, L.S. Bouchard, and B. McMaster, CD19 is functionally and physically associated with surface immunoglobulin, J. Exp. Med. 170: 2159 (1989).

    Article  PubMed  CAS  Google Scholar 

  56. R.J. Schulte, M.-A. Campbell, W.H. Fischer, and B.M. Sefton, Tyrosine phosphorylation of CD22 during B cell activation, Science 258:1001 (1992).

    Article  PubMed  CAS  Google Scholar 

  57. D.A. Tuveson, R.H. Carter, S.P. Soltoff, and D.T. Fearon, CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase, Science 260:986 (1993).

    Article  PubMed  CAS  Google Scholar 

  58. C. Leprince, K.E. Draves, R.L. Geahlen, J.A. Ledbetter, and E.A. Clark, CD22 associates with the human surface IgM-B cell antigen receptor complex, Proc. Natl. Acad. Sci. USA 90: 3236 (1993).

    Article  PubMed  CAS  Google Scholar 

  59. P. Mittelstadt and A.L. DeFranco, Induction of early-response genes by cross-linking membrane immunoglobulin on B lymphocytes, J. Immunol. 150: 4822 (1993).

    PubMed  CAS  Google Scholar 

  60. H. Sun, C.H. Charles, L.F. Lau, and N.K. Tonks, MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo, Cell 75: 487 (1993).

    Article  PubMed  CAS  Google Scholar 

  61. Y. Shi, J.M. Glynn, LJ. Guilbert, T.G. Cotter, R.P. Bissonette, and D.R. Green, Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas, Science 257: 212 (1992).

    Article  PubMed  CAS  Google Scholar 

  62. G.I. Evans, A.H. Wyllie, C.S. Gilbert, T.D. Littlewood, H. Land, M. Brooks, C.M. Waters, L.Z. Penn, and D.C. Hancock, Induction of apoptosis in fibroblasts by c-myc protein, Cell 69: 119 (1992).

    Article  Google Scholar 

  63. J.D. Woronicz, B. Calnan, V. Ngo, and A. Winoto, Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas, Nature 367: 277 (1994).

    Article  PubMed  CAS  Google Scholar 

  64. Z.-G. Liu, S.W. Smith, K.A. McLaughlin, L.M. Schwartz, and B.A. Osborne, Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77, Nature 367: 281 (1994).

    Article  PubMed  CAS  Google Scholar 

  65. J.E. McCormack, V.H. Pepe, R.B. Kent, M. Dean, A. Marshak-Rothstein, and G.E. Sonenshein, Specific regulation of c-myc oncogene expression in a murine B-cell lymphoma, Proc. Natl. Acad. Sci. USA 81: 5546 (1984).

    Article  PubMed  CAS  Google Scholar 

  66. G. Fischer, S.C. Kent, L. Joseph, D.R. Green, and D.W. Scott, Lymphoma models for B cell activation and tolerance. X. Anti-μ mediated growth arrest and apoptosis of murine B cell lymphomas is prevented by the stabilization of myc, J. Exp. Med. 179: 221 (1994).

    Article  PubMed  CAS  Google Scholar 

  67. U. Hibner, L.E. Benhamou, P.-A. Cazenave, and P. Sarthou, Signaling of programmed cell death induction in WEHI-231 B lymphoma cells, Eur. J. Immunol. 23: 2821 (1993).

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Departments of Microbiology & Immunology, University of California, San Francisco, USA

    Anthony L. DeFranco, Paul R. Mittelstadt, Jonathan H. Blum, Tracy L. Stevens, Debbie A. Law, Sandip K. Datta & Linda Matsuuchi

  2. Biochemistry & Biophysics, University of California, San Francisco, USA

    Anthony L. DeFranco & Vivien W.-F. Chan

  3. G. W. Hooper Foundation, University of California, San Francisco, USA

    Anthony L. DeFranco, Paul R. Mittelstadt, Jonathan H. Blum, Tracy L. Stevens, Debbie A. Law, Vivien W.-F. Chan & Sandip K. Datta

  4. Department of Zoology, University of British Columbia, Vancouver, Canada

    Shaun P. Foy & Linda Matsuuchi

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  1. Anthony L. DeFranco
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Editor information

Editors and Affiliations

  1. Department of Medicine, University of California, Irvine, CA, 92717-4069, USA

    Sudhir Gupta

  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892-0001, USA

    William E. Paul

  3. Department of Microbiology and Immunology, University of California, San Francisco, CA, 94143-0552, USA

    Anthony DeFranco

  4. Department of Immunology, University of Washington, Seattle, WA, 98915, USA

    Roger M. Perlmutter

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DeFranco, A.L. et al. (1994). Mechanism of B Cell Antigen Receptor Function: Transmembrane Signaling and Triggering of Apoptosis. In: Gupta, S., Paul, W.E., DeFranco, A., Perlmutter, R.M. (eds) Mechanisms of Lymphocyte Activation and Immune Regulation V. Advances in Experimental Medicine and Biology, vol 365. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0987-9_2

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