The Activation, Proliferation, and Differentiation of Human B Lymphocytes

  • Julian L. AmbrusJr.
  • Cynthia H. Jurgensen
  • Debra L. Bowen
  • Shohken Tomita
  • Toshimasa Nakagawa
  • Naoko Nakagawa
  • Harris Goldstein
  • Normal L. Witzel
  • Howard S. Mostowski
  • Anthony S. Fauci
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 213)


Efforts to evaluate normal human B cell physiology have resulted in the development of a model in which a resting B cell must progress through stages of activation, proliferation, and differentiation before becoming an immunoglobulin (Ig)-producing cell (1–4). Presumably each of these stages has specific signals, positive as well as negative, which control the nature as well as the intensity of the response. To evaluate the validity of this model, researchers have looked for reagents which act selectively at each of these stages. These include antigens, mitogens, soluble factors produced by various cell types, and various pharmacologic agents. In this review we will emphasize some of the studies performed in our laboratory on the various stages of B cell function in humans.


Murine System Lymphoma Line Solubilized Membrane Protein Cell Differentiation Factor Adenylate Cyclase Activator Forskolin 
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. 1.
    R. W. Dutton, R. Falkoff, J. A. Hurst, M. Hoffman, J. W. Kappler, J. R. Ketman, J. R. Lesley, and D. Van. Is there evidence for a non-antibody specific diffusable chemical mediator from the thymus-derived cell in the initiation of the immune response? Prog. Immunol. 1:355 (1971).Google Scholar
  2. 2.
    T. Kishomoto, T. Miyake, Y. Nishizawa, T. Watanabe, and Y. Yamamura. Triggering mechanisms of B lymphocytes. I. Effect of anti-immunoglobulin and enhancing soluble factor on differentiation and proliferation of B cells. J. Immunol. 155:1179(1975).Google Scholar
  3. 3.
    C. D. Parker, J. Fothergill, and D. C. Wadsworth. B lymphocyte activation by insoluble anti-immunoglobulin: induction of immunoglobulin secretion by a T cell dependent soluble factor. J. Immunol. 123:931 (1979).Google Scholar
  4. 4.
    A. Murguchi, J. L. Butler, J. H. Kehrl, and A. S. Fauci. Differential sensitivity of human B cell subsets to activation signals delivered by anti-u antibody and proliferative signals delivered by a monoclonal B cell growth factor. J. Exp. Med. 157:530 (1983).CrossRefGoogle Scholar
  5. 5.
    B. F. Haynes, M. E. Hemler, D. L. Mann, G. S. Eisenbarth, J. Shelhamer, H. S. Mostowski, C. A. Thomas, and A. S. Fauci. Characterization of a monoclonal antibody (4F2) which binds to human monocytes and to a subset of activated lymphocytes. J. Immunol. 126:1409 (1981).Google Scholar
  6. 6.
    B. F. Haynes, M. Hemler, T. Cotner, D. L. Mann, G. S. Eisenbarth, J. L. Strominger, and A. S. Fauci. Characterization of a monoclonal antibody (5E9) which defines a human cell surface surface antigen of cell activation, J. Immunol. 127:347 (1981).Google Scholar
  7. 7.
    T. A. Waldmann, C. K. Goldman, R. J. Robb, J. M. Depper, W. J. Leonard, S. O. Sharrow, K. F. Bongiovanni, S. J. Korsmeyer, and W. G. Green. Expression of interleukin 2 receptors on activated human B cells. J. Exp. Med. 160:1450 (1984).CrossRefGoogle Scholar
  8. 8.
    A. Muraguchi, J. H. Kehrl, D. L. Longo, D. J. Volkman, K. A. Smith, and A. S. Fauci. Interleukin 2 receptors on human B cells. Implications for the role of interleukin 2 in human cell function. J. Exp. Med. 161:181 (1985).CrossRefGoogle Scholar
  9. 9.
    J. H. Kehrl, A. Muraguchi, and A. S. Fauci. Differential expression of cell activation markers following stimulation of resting human B lymphocytes. J. Immunol. 132:2857 (1984).Google Scholar
  10. 10.
    A. Muraguchi, J. H. Kehrl, J. L. Butler, and A. S. Fauci. Sequential requirements for cell cycle progression of resting human B cells after activation by anti-Ig. J. Immunol. 131:176 (1984).Google Scholar
  11. 11.
    A. Muraguchi, and A. S. Fauci. Proliferative responses of normal human B — lymphocytes. Development of an assay system for human B cell growth factor (BCGF). J. Immunol. 129:1104 (1982).Google Scholar
  12. 12.
    L. Meyer, S. M. Fu, and H. G. Kunkel. Regulation of B cell activation and differentiation with factors generated by human T cell hybridomas. Immunol. Rev. 78:119(1984).CrossRefGoogle Scholar
  13. 13.
    C. B. Thompson, M. E. Shaefer, F. D. Finkelman, I. Scher, J. Farrar, and J. J. Mond. T cell derived B cell growth factors can innduce stimulation of both resting and activated B cells. J. Immunol. 134:369 (1985).Google Scholar
  14. 14.
    D. L. Bowen, J. L. Ambrus Jr, and A. S. Fauci. Identification and characterization of a B cell activation factor (BCAF) produced by a human T cell line. J. Immunol. in press.Google Scholar
  15. 15.
    J. L. Butler, A. Muraguchi, H. C. Lane, and A. S. Fauci. Development of a human T-T hybridoma secreting B cell growth factor. J. Exp. Med. 157:601 (1983).CrossRefGoogle Scholar
  16. 16.
    T. R. Cupps, T. L. Gerrard, R. J. M. Falkoff, G. Whalen, and A. S. Fauci. Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation. J. Clin. Invest. 75:754 (1985).CrossRefGoogle Scholar
  17. 17.
    D. L. Bowen, and A. S. Fauci. Selective suppressive effects of glucocorticoids on the early events in the human B cell activation process. J. Immunol. 133:1885 (1984).Google Scholar
  18. 18.
    A. S. Fauci, K. R. Pratt, and G. Whalen. Activation of human B lymphocytes. IV. Regulatory effects of corticosteroids on the triggering signal in the plaque-forming cell response of human peripheral blood B lymphocytes to polyclonal activation. J. Immunol. 119:598 (1977).Google Scholar
  19. 19.
    J. Grayon, N. J. Dooley, I. R. Koski, and R. M. Blaese. Immunoglobulin production induced in vitro by glucocorticoid hormones. T cell dependent stimulation of immunoglobulin production without B cell proliferation in cultures of human peripheral blood lymphocytes. J. Clin. Invest. 68:1539 (1981).CrossRefGoogle Scholar
  20. 20.
    A. Muraguchi, J. L. Butler, J. H. Kehrl, R. J. M. Falkoff and A. S. Fauci. Selective suppression of an early step in human B cell activation with cyclosporin A. J. Exp. Med. 158:690 (1983).CrossRefGoogle Scholar
  21. 21.
    A. Muraguchi, K. Miyazaki, J. H. Kehrl, and A. S. Fauci. Inhibition of human B cell activation by diterpine forskolin: interference with B cell growth factor-induced G1 to S transition of the B cell cycle. J. Immunol. 133:1283 (1984).Google Scholar
  22. 22.
    R. J. M. Falkoff, A. Muraguchi, J-X Hong, J. L. Butler, C. A. Dinarello, and A. S. Fauci. The effects of interleukin-1 on human B cell activation and proliferation. J. Immunol. 131:801 (1983).Google Scholar
  23. 23.
    P. E. Lipsky, P. A. Thompson, L. J. Rossenwasser, and C. A. Dinarello. The role of interleukin 1 in human B cell activation: inhibition of B cell proliferation and the generation of immunoglobulin-secreting cells by an antibody against human leukocyte pyrogen. J. Immunol. 130:2708 (1983).Google Scholar
  24. 24.
    H. Harada, K. Shioiri-Nakanop, M. Moyumi and T. Kowai. Distinction of two subtypes of human leukocyte interferon (IFN-) on B cell activation. B cell proliferation by two subtypes of IFN-. J. Immunol. 131:238 (1983).Google Scholar
  25. 25.
    R. H. Zubler, J. W. Lowenthal, F. Erard, N. Hashimoto, R. Devos, and H. R. MacDonald. Activated B cells express receptors for, and proliferate in response to, pure interleukin 2. J. Exo.Med. 160:1170 (1984).CrossRefGoogle Scholar
  26. 26.
    Le Thi Bich-Thuy, H. C. Lane, and A. S. Fauci. Human B-cell prolifeation in response to recombinant interleukin 2 is not due to T-cell help. Cell Immunol. 94:353 (1985).CrossRefGoogle Scholar
  27. 27.
    T. Kishimoto, K. Yoshizaki, M. Okada, T. Kuritani, H. Kikutani, N. Sakaguchi, Y. Miki, H. Kishi, T. Nakagawa, K. Shjimizu, K. Fukunaga and T. Taga. Growth and differentiation factors and activation of human B cells. In Lymphokines, Vol. 10, M. H. Schreier, K. A. Smith eds. Acacdemic Press, New York (1985) pp. 15.Google Scholar
  28. 28.
    M. Fresno, H. DerSimonion, G. Nabel, and H. Cantor. Proteins synthesized by inducer T cells: evidence for a mitogenic peptide shared by inducer molecules that stimulate different cell types. Cell 30:707 (1982).CrossRefGoogle Scholar
  29. 29.
    C. G. Sahasrabuddhe, J. Morgan, S. Sharma, S. Mehta, B. Martin, D. Wright and A. Maizel. Evidence for an intracellular precursor for human B-cell growth factor. Proc. Natl. Acad.Sci. USA 81:7902 (1984).ADSCrossRefGoogle Scholar
  30. 30.
    S. R. Mehta, D. Conrad, R. Sandler, J. Morgan, R. Montagna, and A. L. Maizel. Purification of human B cell growth factor. J. Immunol. 135:3298 (1985).Google Scholar
  31. 31.
    D. J. Volkman, M. Popovic, R. C. Gallo, and A. S. Fauci. Human T cell leukemia/lymphoma virus-infected antigen-specific T cell clones: indiscriminate helper function and lymphokine production. J. Immunol. 134:4237 (1985).Google Scholar
  32. 32.
    J. L. Ambrus Jr, C. H. Jurgensen, E. J. Brown, and A. S. Fauci. Purification to homogeneity of a high molecular weight human B cell growth factor, demonstration of specific binding to activated B cells, and development of a monoclonal antibody to the factor. J. Exp. Med. 162:1319 (1985).CrossRefGoogle Scholar
  33. 33.
    J. L. Ambrus Jr, C. H. Jurgensen, E. J. Brown, U. K. Siebenlist and A. S. Fauci. Monoclonal antibody distinguishes distinct B cell growth factors produced by normal T cells. Clin. Res. 33:55A (1985).Google Scholar
  34. 34.
    J. L. Ambrus Jr, and A. S. Fauci. Human B lymphoma cell line producing B cell growth factor. J. Clin. Invest. 75:732 (1985).CrossRefGoogle Scholar
  35. 35.
    B. A. Blazer, L. M. Sutton, and M. Strome. Self-stimulating growth factor production by B-cell lines derived from Burkitt’s lymphomas and other lines transformed in vitro by Epstein-Barr virus. Cancer Res. 43:4562 (1983).Google Scholar
  36. 36.
    J. Gordon, S. C. Ley, D. Melamed, L. C. English, and. N. C. Hughes-Jones. Immortalized B lymphocytes produce B cell growth factor. Nature 310:145 (1984).ADSCrossRefGoogle Scholar
  37. 37.
    H. S. Mostowski, J. L. Ambrus Jr, D. J. Volkman, and A. S. Fauci. Cloning of both B cell growth factor (BCGF) producer and responder cells from a human B cell line. Fed. Proc. 44:1868 (1985).Google Scholar
  38. 38.
    N. L. Witzel, J. L. Ambrus Jr, C. H. Jurgensen, H. S. Mostowski, and A. S. Fauci. Monoclonal antibody recognizing a subpopulation of human B lymphocytes producing B cell growth factor (BCGF). Proc. 6th Int. Congress Immunol., in press.Google Scholar
  39. 39.
    C. H. Jurgensen, J. L. Ambrus Jr, and A. S. Fauci. Production of B cell growth factor by normal human B cells. Fed. Proc. 44:573 (1985).Google Scholar
  40. 40.
    J. L. Ambrus Jr, C. H. Jurgensen, E. J. Brown, N. L. Witzel, and A. S. Fauci. Monoclonal antibody recognizing a cell surface antigen on activated human B lymphocytes intimately associated with a receptor for B cell growth factor (BCGF). Fed. Proc. in press.Google Scholar
  41. 41.
    L. K. L. Jung, and S. M. Fu. Selective inhibition of growth factor-dependent human B cell proliferation by monoclonal antibody AB-1 to an antigen expressed by activated B cells. J. Exp. Med. 160:1919 (1984).CrossRefGoogle Scholar
  42. 42.
    T. Hirano, T. Teranishi, B. Lin, and K. Onoue. Human helper T factors. IV. Demonstration of a human late-acting B cell ifferentiation factor acting on Staphylococcus aureus Cowan I-stimulated B cells. J. Immunol. 133:798 (1984).Google Scholar
  43. 43.
    H. Goldstein, D. J. Volkman, J. L. Ambrus Jr, and A. S. Fauci. Characterization of a T4+/Leu-8+ T cell clone that directly helps B cell Ig production by secreting B cell differentiation factor. J. Immunol. 135:339 (1985).Google Scholar
  44. 44.
    K. L. Shimizu, T. Hirano, K. Ishibashi, N. Nakano, T. Taga, K. Sugamura, Y. Yamamura, and T. Kishimoto. Immortalization of BGDF (BCGF II)- and BCDF-producing T cells by human T cell leukemia virus (HTLV) and characterization of human BGDF (BCDF II). J. Immunol. 134:1728 (1985).Google Scholar
  45. 45.
    T. Kishomoto, K. Yoshizaki, M. Kimoto, M. Okada, T. Kuritani, H. Kikutani, K. Shimizu, T. Nakagawa, N. Nakagawa, Y. Miki, H. Kishi, K. Fukunaga, T. Yoshikubo, and T. Taga. B cell growth and differentiation factors and mechanism of B cell activation. Immunol. Rev. 78:97 (1984).CrossRefGoogle Scholar
  46. 46.
    J. L. Butler, R. J. M. Falkoff, and A. S. Fauci. Development of a human T cell hybridoma secreting separate B cell growth and differentiation factors. Proc. Natl. Acad. Sci. USA 81:2475 (1984).ADSCrossRefGoogle Scholar
  47. 47.
    E. S. Vitetta, J. Ohara, C. D. Myers, J. E. Layton, P. H. Krammer, and W. E. Paul. Serological, biochemical, and functional identity of B cell-stimulatory factor I and B cell differentiation factor for IgGl. J. Exp. Med. 162:1726 (1985).CrossRefGoogle Scholar
  48. 48.
    S. Tomita, J. L. Ambrus Jr, D. J. Volkman, D. L. Longo, H. Mitsuya, M. S. Reitz Jr, and A. S. Fauci. Human T cell leukemia/lymphoma virus I infection and subsequent cloning of normal human B cells. Direct responsiveness of cloned cells to recombinant interleukin 2 by differentiation in the absence of enhanced proliferation. J. Exp. Med. 162:393 (1985).CrossRefGoogle Scholar
  49. 49.
    P. Ralph, G. Jeong, K. Weite, R. Mertelsmann, H. Rabin, L. E. Henderson, L. M. Souza, T. C. Boone, and R. J. Robb. Stimulation of immunoglobulin secretion in human B lymphocytes as a direct effect of high concentrations of IL-2. J. Immunol. 133:2442 (1984).Google Scholar
  50. 50.
    T. Nakagawa, N. Nakagawa, D. J. Volkman, and A. S. Fauci. Sequential synergistic effect of interleukin 2 and interferon- on the differentiation of a Tac-antigen-positive B cell line. J. Immunol. 136:164 (1986).Google Scholar
  51. 51.
    T. Teranishi, T. Hirano, B-H Lin, and K. Onoue. Demonstration of the involvement of interleukin 2 in the differentiation of Staphylococcus aureus Cowan I-stimulated B cells. J. Immunol. 133:3062 (1984).Google Scholar
  52. 52.
    T. Nakagawa, T. Hirano, N. Nakagawa, K. Yoshizaki, and T. Kishimoto. Effect of recombinant IL 2 and IFN- on proliferation and differentiation of human B cells. J.Immunol. 134:959 (1985).Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Julian L. AmbrusJr.
    • 1
  • Cynthia H. Jurgensen
    • 1
  • Debra L. Bowen
    • 1
  • Shohken Tomita
    • 1
  • Toshimasa Nakagawa
    • 1
  • Naoko Nakagawa
    • 1
  • Harris Goldstein
    • 1
  • Normal L. Witzel
    • 1
  • Howard S. Mostowski
    • 1
  • Anthony S. Fauci
    • 1
  1. 1.Laboratory of Immunoregulation, National Institute of Allergy and Infectious DiseasesNational Institutes of Health BethesdaUSA

Personalised recommendations