Inducible Resistance to Fas-Mediated Apoptosis in Primary B Lymphocytes

  • Thomas L. Rothstein
  • Linda C. Foote
  • Thomas J. Schneider
  • Gavin M. Fischer
  • Bruce A. Jacobson
  • David H. Lynch
  • Shry-Te Ju
  • Ann Marshak-Rothstein
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 406)


The regulated initiation of programs leading to cell death is responsible, at least in part, for maintaining homeostasis within the immune system. Two general mechanisms for the production of cytotoxicity in susceptible targets by T effector cells have been described, one involving Ca++ dependent, perforin/granzyme exocytosis, and the other involving Fas antigen (CD95) engagement1. Fas functions in target cells as a receptor that signals for apoptosis, and Fas has been implicated in the process of reducing lymphocyte numbers following acute immune responses, termed activation induced cell death2–8. Although classical CD8+ cytotoxic T lymphocytes have recently been shown to express both types of cytotoxic activity, a distinct class of T cells, with the phenotype of CD4+ Th1 cells, mediates target cell death primarily in a Fas-dependent fashion9–14.


Phorbol Myristate Acetate Antigen Receptor Phorbol Myristate Acetate Intracellular Change Acute Immune Response 
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  1. 1.
    G. Berke. The CTL’s kiss of death. Cell 81: 9 (1995).PubMedCrossRefGoogle Scholar
  2. 2.
    S. Yonehara, A. Ishii, and M. Yonehara. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J. Exp. Med. 169: 1747 (1989).PubMedCrossRefGoogle Scholar
  3. 3.
    B. C. Trauth, C. Klas, A. M. J. Peters, S. Matzku, P. Moller, W. Falk, K.-M. Debatin, and P. H. Krammer. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245: 301. (1989).PubMedCrossRefGoogle Scholar
  4. 4.
    C. Watanabe-Fukunaga, I. Brannan, N. G. Copeland, N. A. Jenkins, and S. Nagata. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314. (1992).PubMedCrossRefGoogle Scholar
  5. 5.
    S.-T. Ju, D. J. Panka, H. Cui, R. Ettinger, M. El-Khatib, D. H. Sherr, B. Z. Stanger, and A. Marshak-Rothstein. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373: 444. (1995).PubMedCrossRefGoogle Scholar
  6. 6.
    J. Dhein, H. Walczak, C. Baumler, K.-M. Debatin, and P. H. Krammer. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373: 438. (1995).PubMedCrossRefGoogle Scholar
  7. 7.
    T. Brunner, R. J. Mogil, D. LaFace, N. J. Yoo, A. Mahboubi, F. Echeverri, S. J. Martin, W. R. Force, D. H. Lynch, C. F. Ware, and D. R. Green. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373: 441. (1995).PubMedCrossRefGoogle Scholar
  8. 8.
    S. Nagata, and P. Golstein. The Fas death factor. Science 267: 1449. (1995).PubMedCrossRefGoogle Scholar
  9. 9.
    D. Kägi, F. Vignaux, B. Lederemann, K. Bürki, V. Depraetere, S. Nagata, H. Hengartner, and P. Golstein. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265: 528 (1994).PubMedCrossRefGoogle Scholar
  10. 10.
    B. Lowin, M. Hahne, C. Mattmann, and J. Tschopp. Cytolytic T-cll cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370: 650 (1994).PubMedCrossRefGoogle Scholar
  11. 11.
    E. Rouvier, M.-F. Luciani, and P. Golstein. Fas involvement in Cat+-independent T cell-mediated cytotoxicity. J. Exp. Med. 177: 195 (1993).PubMedCrossRefGoogle Scholar
  12. 12.
    T. Stalder, S. Hahn, and P. Erb. Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J. Immunol. 152: 1127 (1994).PubMedGoogle Scholar
  13. 13.
    S.-T. Ju, H. Cui, D. J. Panka, R. Ettinger, and A. Marshak-Rothstein. Participation of target Fas protein in apoptosis pathway induced by CD4+ Thl and CD8+ cytotoxic T cells. Proc. Natl. Acad. Sci. USA 91: 4185 (1994).PubMedCrossRefGoogle Scholar
  14. 14.
    S. Hanabuchi, M. Koyanagi, A. Kawasaki, N. Shinohara, A. Matsuzawa, Y. Nishimura, Y. Kobayashi, S. Yonehara, H. Yagita, and K. Okumura. Fas and its ligand in a general mechanism of T-cell-mediated cytotoxicity. Proc. Natl. Acad. Sci. USA 91: 4930 (1994).PubMedCrossRefGoogle Scholar
  15. 15.
    P. Erb, D. Grogg, M. Troxler, M. Kennedy, and M. Fluri. CD4+ T cell-mediated killing of MHC class II-positive antigen-presenting cells. I. Characterization of target cell recognition by in vivo or in vitro activated CD4+ killer T cells. J. Immunol. 144: 790 (1990).PubMedGoogle Scholar
  16. 16.
    L. B. Owen-Schaub, S. Yonehara, W. L. Crump III, and E. A. Grimm. DNA fragmentation and cell death is selectively triggered in activated human lymphocytes by Fas antigen engagement. Cell. Immunol. 140: 197 (1992).PubMedCrossRefGoogle Scholar
  17. 17.
    Daniel, P. T., and P. H. Krammer. Activation induces sensitivity toward APO-1 (CD95)-mediated apoptosis in human B cells. J. Immunol. 152: 5624. (1994).PubMedGoogle Scholar
  18. 18.
    Rothstein, T. L., J. K. M. Wang, D. J. Panka, L. C. Foote, Z. Wang, B. Stanger, H. Cui, S.-T. Ju, and A. Marshak-Rothstein. Protection against Fas-dependent Thl-mediated apoptosis by antigen receptor engagement in B cells. Nature 374: 163 (1995).PubMedCrossRefGoogle Scholar
  19. 19.
    K. Kawakami, and D. C. Parker. Antigen and helper T lymphocytes activate B lymphocytes by distinct signaling pathways. Eur. J. Immunol. 23: 77 (1993).PubMedCrossRefGoogle Scholar
  20. 20.
    H. Xie, and T. L. Rothstein. Protein kinase C mediates activation of nuclear cAMP response element-binding protein (CREB) in B lymphocytes stimulated through surface Ig. J. Immunol. 154: 1717 (1995).PubMedGoogle Scholar
  21. 21.
    L. Huo, and T. L. Rothstein. Receptor-specific induction of individual AP-1 components in B lymphocytes. J. Immunol. 154: 3300 (1995).PubMedGoogle Scholar
  22. 22.
    J. C. Cambier, C. M. Pleiman, and M. R. Clark. Signal transduction by the B cell antigen receptor and its coreceptors. Ann. Rev. Immunol. 12: 457 (1994).CrossRefGoogle Scholar
  23. 23.
    T. Kato, T. Kokuho, T. Tamura, and H. Nariuchi. Mechanisms of T cell contact-dependent B cell activation. J. Immunol. 152: 2130 (1994).PubMedGoogle Scholar
  24. 24.
    L. S. Marshall, D. M. Shepherd, J. A. Ledbetter, a. Aruffo, and R. J. Noelle. Signaling events during helper T cell-dependent B cell activation. I. Analysis of the signal transduction pathways triggered by activated helper T cells in resting B cells. J. Immunol. 152: 4816 (1994).PubMedGoogle Scholar
  25. 25.
    A.-C. Lalmanach-Girard, T. C. Chiles, D. C. Parker, and T. L. Rothstein. T cell-dependent induction of NF-KB in B cells. J. Exp. Med. 177: 1215 (1993).PubMedCrossRefGoogle Scholar
  26. 26.
    D. A. Francis, J. G. Karras, X. Ke, R. Sen, and T. L. Rothstein. Induction of the transcription factors NF-KB, AP-1 and NF-AT during B cell stimulation through the CD40 receptor. Intl. Immunol. 7: 151 (1995).CrossRefGoogle Scholar
  27. 27.
    J. J. Mond, N. Feuerstein, F. D. Finkelman, F. Huang, K.-P. Huang, and G. Dennis. B-lymphocyte activation mediated by anti-immunoglobulin antibody in the absence of protein kinase C. Proc. Natl. Acad. Sci. USA 84: 8588 (1987).PubMedCrossRefGoogle Scholar
  28. 28.
    J. Liu, T. C. Chiles, R. Sen, and T. L. Rothstein. Inducible nuclear expression of NF-KB in primary B cells stimulated through the surface Ig receptor. J. Immunol. 146: 1685 (1991).PubMedGoogle Scholar
  29. 29.
    H. Hidaka, M. Inagaki, S. Kawamoto, and Y. Sasaki. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochem. 23: 5036 (1984).CrossRefGoogle Scholar
  30. 30.
    G. G. B. Klaus, A. O’Garra, M. K. Bijsterbosch, and M. Holman. Activation and proliferation signals in mouse B cells. VIII. Induction of DNA synthesis in B cells by a combination of calcium ionophores and phorbol myristate acetate. Eur. J. Immunol. 16: 92 (1986).PubMedCrossRefGoogle Scholar
  31. 31.
    T. L. Rothstein, T. R. Baeker, R. A. Miller, and D. L. Kolber. Stimulation of murine B cells by the combination of calcium ionophore plus phorbol ester. Cell. Immunol. 102: 364 (1986).PubMedCrossRefGoogle Scholar
  32. 32.
    W. M. Flanagan, B. Corthesy, R. J. Bram, and G. R. Crabtree. Nuclear association of a T cell transcription factor blocked by FK506 and cyclosporin A. Nature 352: 803 (1991).PubMedCrossRefGoogle Scholar
  33. 33.
    L. Venkataraman, D. A. Francis, Z. Wang, J. Liu, T. L. Rothstein, and R. Sen. Cyclosporin-A sensitive induction of NF-AT in murine B cells. Immunity 1: 189 (1994).PubMedCrossRefGoogle Scholar
  34. 34.
    H. Xie, Z. Wang, and T. L. Rothstein. Signaling pathways for antigen receptor-mediated induction of transcription factor CREB in B lymphocytes. Cell. Immunol.,in press (1996).Google Scholar
  35. 35.
    S. Nagata, and T. Suda. Fas and Fas ligand: 1pr and gld mutations. Immunol. Today 16: 39 (1995).PubMedCrossRefGoogle Scholar
  36. 36.
    J. Ogasawara, R. Watanabe-Fukunaga, M. Adachi, A. Matsuzawa, T. Kasugai, Y. Kitamura, N. Itoh, T. Suda, and S. Nagata. Lethal effect of the anti-Fas antibody in mice. Nature 364: 806 (1993).PubMedCrossRefGoogle Scholar
  37. 37.
    J. C. Unkeless. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J. Exp. Med. 150: 580 (1979).PubMedCrossRefGoogle Scholar
  38. 38.
    T. Sato, M. Hanada, S. bodrug, S. Irie, N. Iwama, L. H. Boise, C. B. Thompson, E. Golemis, L. Fong, H.-G. Wang, and J. C. Reed. Interactions among members of the Bc1–2 protein family analyzed with a yeast two-hybrid system. Proc. Natl. Acad. Sci. USA 91: 9238 (1994).PubMedCrossRefGoogle Scholar
  39. 39.
    G. Núflez, R. Merino, D. Grillot, and M. Gonzalez-Garcia. Bc1–2 and Bcl-x: regulatory switches for lymphoid death and survival. Immunol. Today 15: 582 (1994).CrossRefGoogle Scholar
  40. 40.
    S. Cory. Regulation of lymphocyte survival by the Bc1–2 gene family. Ann. Rev. Immunol. 13: 513 (1995).CrossRefGoogle Scholar
  41. 41.
    L. H. Boise, M. Gonzalez-Garcia, C. e. Postema, L. Ding, T. Lindsten, L. A. Turka, X. Mao, G. Núnez, and C. B. Thompson. bel-x, a óc1–2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74: 597 (1993).PubMedCrossRefGoogle Scholar
  42. 42.
    D. T. Chao, G. P. Linette, L. H. Boise, L. S. White, C. B. Thompson, and S. J. Korsmeyer. Bc1-xL and Bc1–2 repress a common pathway of cell death. J. Exp. Med. 182: 821 (1995).PubMedCrossRefGoogle Scholar
  43. 43.
    E. Gulbins, R. Bissonnette, A. Mahboubi, S. Martin, W. Nishioka, T. Brunner, G. Baier, G. Baier-Bitterlich, C. Byrd, F. Lang, R. Kolesnick, A. Altman, and D. Green. FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 2: 341 (1995).PubMedCrossRefGoogle Scholar
  44. 44.
    C. G. Tepper, S. Jayadev, B. Liu, A. Bielawska, R. Wolff, S. Yonehara, Y. A. Hannun, and M. F. Seldin. Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity. Proc. Natl. Acad. Sci. USA 92: 8443 (1995).CrossRefGoogle Scholar
  45. 45.
    W. E. Paul, and J. Ohara. B-cell stimulatory factor- 1 /interleukin 4. Ann. Rev. Immunol. 5: 429 (1987).CrossRefGoogle Scholar
  46. 46.
    J. Ohara, and W. E. Paul. B cell stimulatory factor BSF-1: Production of a monoclonal antibody and molecular characterization. Nature 315: 333 (1985).PubMedCrossRefGoogle Scholar
  47. 47.
    A. D. Keegan, K. Nelms, L.-M. Wang, J. H. Pierece, and W. E. Paul. Interleukin 4 receptor: signaling mechanisms. Immunol. Today 15: 423 (1994).PubMedCrossRefGoogle Scholar
  48. 48.
    M. Dancescu, C. Wu, M. Rubio, G. Delespesse, and M. Sarfati. IL-4 induces conformational change of CD20 antigen via a protein kinase C-independent pathway. Antagonistic effect of anti-CD40 monoclonal antibody. J. Immunol. 148: 2411 (1992).PubMedGoogle Scholar
  49. 49.
    C. E. Lee, S. R. Yoon, and K. H. Pyun. Interleukin-4 signals regulating CD23 gene expression in human B cells: protein kinase C-independent signaling pathways. Cell. Immunol. 146: 171 (1993).PubMedCrossRefGoogle Scholar
  50. 50.
    I. A. C. MacLennan. Germinal centers. Ann. Rev. Immunol. 12: 117 (1994).CrossRefGoogle Scholar
  51. 51.
    S. L. Parry, J. Hasbold, M. Holman, and G. G. B. Klaus. Hypercross-linking surface IgM or IgD receptors on mature B cells induces apoptosis that is reversed by costimulation with IL-4 and anti-CD40. J. Immunol. 152: 2821 (1994).PubMedGoogle Scholar
  52. 52.
    B. E. Wilson, E. Mochon, and L. M. Boxer. Induction of bcl-2 expression by phosphorylated CREB proteins during B cell activation. Blood 86: 327a (1995).Google Scholar
  53. 53.
    B. A. Jacobson, D. J. Panka, K.-A. Nguyen, J. Erikson, A. K. Abbas, and A. Marshak-Rothstein. Anatomy of autoantibody production: dominant localization of antibody-producing cells to T cell zones in Fas-deficient mice. Immunity 3: 509 (1995).PubMedCrossRefGoogle Scholar
  54. 54.
    J. C. Rathmell, M. P. Cooke, W. Y. Ho, J. Grein, S. E. Townsend, M. M. Davis, and C. C. Goodnow. CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4’ T cells. Nature 376: 181 (1995).PubMedCrossRefGoogle Scholar
  55. 55.
    G. J. V. Nossal. Negative selection of lymphocytes. Cell 76: 229 (1994).PubMedCrossRefGoogle Scholar
  56. 56.
    M. P. Cooke, A. W. Heath, K. M. Shokat, Y. Zeng, F. D. Finkelman, P. s. Linsley, M. Howard, and C. C. Goodnow. Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. J. Exp. Med. 179: 425 (1994).PubMedCrossRefGoogle Scholar
  57. 57.
    J. M. Eris, A. Basten, R. Brink, K. Doherety, M. R. Kehry, and P. D. Hodgkin. Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions. Proc. Natl. Acad. Sci. USA 92: 4392 (1994).CrossRefGoogle Scholar
  58. 58.
    C. C. Goodnow, J. Crosbie, H. Jorgensen, R. A. Brink, and A. Basten. Induction of self-tolerance in mature peripheral B lymphocytes. Nature 342: 385 (1989).PubMedCrossRefGoogle Scholar
  59. 59.
    W. E. Paul, and R. A. Seder. Lymphocyte responses and cytokines. Cell 76: 241 (1994).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Thomas L. Rothstein
    • 1
    • 2
  • Linda C. Foote
    • 2
  • Thomas J. Schneider
    • 2
  • Gavin M. Fischer
    • 2
  • Bruce A. Jacobson
    • 2
  • David H. Lynch
    • 3
  • Shry-Te Ju
    • 1
    • 4
  • Ann Marshak-Rothstein
    • 2
    • 4
  1. 1.The Department of Medicine and The Evans Memorial Department of Clinical ResearchBoston University Medical CenterBostonUSA
  2. 2.The Department of MicrobiologyBoston University Medical CenterBostonUSA
  3. 3.Department of ImmunobiologyImmunex Research and Development CorporationSeattleUSA
  4. 4.The Department of PathologyBoston University Medical CenterBostonUSA

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