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. 1992 Mar 1;175(3):671–682. doi: 10.1084/jem.175.3.671

Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A

PMCID: PMC2119142  PMID: 1371300

Abstract

In the present report, we have investigated the in vitro differentiation of surface(s) sIgD+ and sIgD- human B cells into Ig- secreting cells in response to various stimuli. sIgD+ B cells homogeneously expressed some of the antigens identifying mantle zone B cells, but lacked expression of germinal center markers, thus confirming that the B cell populations positively selected on the basis of sIgD expression were highly enriched for naive B lymphocytes. Conversely, sIgD- B cells expressed some of the antigens specifically associated with germinal center B cells. T cell-independent differentiation of sIgD+ and sIgD- B cells could be achieved by simultaneous crosslinking of sIgs and CD40 in the presence of a mouse Ltk- cell line stably expressing human CDw32/Fc gamma RII (CDw32 L cells). In this experimental system, sIgD+ B cells were exclusively proned for IgM synthesis, whereas sIgD- B cells produced IgG, IgM, and IgA. Both the human and viral forms of interleukin 10 (IL-10) strongly increased the Ig secretion by sIgD+ and sIgD- B cells simultaneously activated through sIgs and CD40. IgM and IgG constituted the predominant Ig isotype produced by sIgD+ and sIgD- B cells, respectively, in response to IL-10. sIgD+ B cells could be induced for IgA synthesis upon co-culturing with transforming growth factor beta (TGF-beta) and IL-10, in the presence of an anti-CD40 monoclonal antibody presented by the CDw32 L cells. In contrast, TGF-beta suppressed the IL-10-mediated IgG, IgM, and IgA secretions by sIgD- B cells. sIgD+ B cells could not be induced for IgA synthesis by TGF-beta and IL-10 after crosslinking of their sIgs, suggesting that ligation of CD40 was one of the obligatory signals required for commitment of naive B cells to IgA secretion. Limiting dilution experiments indicated that the IgA-potentiating effect of TGF-beta was due to its capacity to increase the frequency of IgA-producing cells, most likely as a consequence of class switching. Taken together, our data strongly suggest that TGF-beta is involved in the regulation of IgA isotype selection in humans.

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Selected References

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  1. Bonnefoy J. Y., Aubry J. P., Peronne C., Wijdenes J., Banchereau J. Production and characterization of a monoclonal antibody specific for the human lymphocyte low affinity receptor for IgE: CD 23 is a low affinity receptor for IgE. J Immunol. 1987 May 1;138(9):2970–2978. [PubMed] [Google Scholar]
  2. Boyd A. W., Freedman A. S., Horowitz J. C., Anderson K. C., Fisher D. C., Rosen K. J., Schlossman S. F., Nadler L. M. Studies of the in vitro activation and differentiation of human B lymphocytes. II. Optimization of activation by anti-immunoglobulin antibody bound to beads: analysis of the role of autocrine effects on B-cell proliferation and of T-cell help in B-cell differentiation. Cell Immunol. 1986 Apr 15;99(1):228–240. doi: 10.1016/0008-8749(86)90231-5. [DOI] [PubMed] [Google Scholar]
  3. Chrétien I., Pène J., Brière F., De Waal Malefijt R., Rousset F., De Vries J. E. Regulation of human IgE synthesis. I. Human IgE synthesis in vitro is determined by the reciprocal antagonistic effects of interleukin 4 and interferon-gamma. Eur J Immunol. 1990 Feb;20(2):243–251. doi: 10.1002/eji.1830200203. [DOI] [PubMed] [Google Scholar]
  4. Clark E. A., Ledbetter J. A. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4494–4498. doi: 10.1073/pnas.83.12.4494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clement L. T., Dagg M. K., Gartland G. L. Small, resting B cells can be induced to proliferate by direct signals from activated helper T cells. J Immunol. 1984 Feb;132(2):740–744. [PubMed] [Google Scholar]
  6. Coffman R. L., Lebman D. A., Shrader B. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med. 1989 Sep 1;170(3):1039–1044. doi: 10.1084/jem.170.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Defrance T., Vanbervliet B., Pène J., Banchereau J. Human recombinant IL-4 induces activated B lymphocytes to produce IgG and IgM. J Immunol. 1988 Sep 15;141(6):2000–2005. [PubMed] [Google Scholar]
  8. Gadol N., Peacock M. A., Ault K. A. Antigenic phenotype and functional characterization of human tonsil B cells. Blood. 1988 Apr;71(4):1048–1055. [PubMed] [Google Scholar]
  9. Gascan H., Gauchat J. F., Roncarolo M. G., Yssel H., Spits H., de Vries J. E. Human B cell clones can be induced to proliferate and to switch to IgE and IgG4 synthesis by interleukin 4 and a signal provided by activated CD4+ T cell clones. J Exp Med. 1991 Mar 1;173(3):747–750. doi: 10.1084/jem.173.3.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gauchat J. F., Lebman D. A., Coffman R. L., Gascan H., de Vries J. E. Structure and expression of germline epsilon transcripts in human B cells induced by interleukin 4 to switch to IgE production. J Exp Med. 1990 Aug 1;172(2):463–473. doi: 10.1084/jem.172.2.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hsu D. H., de Waal Malefyt R., Fiorentino D. F., Dang M. N., Vieira P., de Vries J., Spits H., Mosmann T. R., Moore K. W. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science. 1990 Nov 9;250(4982):830–832. doi: 10.1126/science.2173142. [DOI] [PubMed] [Google Scholar]
  12. Iwasato T., Shimizu A., Honjo T., Yamagishi H. Circular DNA is excised by immunoglobulin class switch recombination. Cell. 1990 Jul 13;62(1):143–149. doi: 10.1016/0092-8674(90)90248-d. [DOI] [PubMed] [Google Scholar]
  13. Jabara H. H., Fu S. M., Geha R. S., Vercelli D. CD40 and IgE: synergism between anti-CD40 monoclonal antibody and interleukin 4 in the induction of IgE synthesis by highly purified human B cells. J Exp Med. 1990 Dec 1;172(6):1861–1864. doi: 10.1084/jem.172.6.1861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jelinek D. F., Lipsky P. E. Regulation of human B lymphocyte activation, proliferation, and differentiation. Adv Immunol. 1987;40:1–59. doi: 10.1016/s0065-2776(08)60237-0. [DOI] [PubMed] [Google Scholar]
  15. Kehrl J. H., Roberts A. B., Wakefield L. M., Jakowlew S., Sporn M. B., Fauci A. S. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol. 1986 Dec 15;137(12):3855–3860. [PubMed] [Google Scholar]
  16. Kehrl J. H., Thevenin C., Rieckmann P., Fauci A. S. Transforming growth factor-beta suppresses human B lymphocyte Ig production by inhibiting synthesis and the switch from the membrane form to the secreted form of Ig mRNA. J Immunol. 1991 Jun 1;146(11):4016–4023. [PubMed] [Google Scholar]
  17. Ledbetter J. A., Clark E. A. Surface phenotype and function of tonsillar germinal center and mantle zone B cell subsets. Hum Immunol. 1986 Jan;15(1):30–43. doi: 10.1016/0198-8859(86)90315-0. [DOI] [PubMed] [Google Scholar]
  18. Lundgren M., Persson U., Larsson P., Magnusson C., Smith C. I., Hammarström L., Severinson E. Interleukin 4 induces synthesis of IgE and IgG4 in human B cells. Eur J Immunol. 1989 Jul;19(7):1311–1315. doi: 10.1002/eji.1830190724. [DOI] [PubMed] [Google Scholar]
  19. Matsuoka M., Yoshida K., Maeda T., Usuda S., Sakano H. Switch circular DNA formed in cytokine-treated mouse splenocytes: evidence for intramolecular DNA deletion in immunoglobulin class switching. Cell. 1990 Jul 13;62(1):135–142. doi: 10.1016/0092-8674(90)90247-c. [DOI] [PubMed] [Google Scholar]
  20. Miltenyi S., Müller W., Weichel W., Radbruch A. High gradient magnetic cell separation with MACS. Cytometry. 1990;11(2):231–238. doi: 10.1002/cyto.990110203. [DOI] [PubMed] [Google Scholar]
  21. Miyawaki T., Butler J. L., Radbruch A., Gartland G. L., Cooper M. D. Isotype commitment of human B cells that are transformed by Epstein-Barr virus. Eur J Immunol. 1991 Jan;21(1):215–220. doi: 10.1002/eji.1830210132. [DOI] [PubMed] [Google Scholar]
  22. Noelle R. J., Snow E. C. Cognate interactions between helper T cells and B cells. Immunol Today. 1990 Oct;11(10):361–368. doi: 10.1016/0167-5699(90)90142-v. [DOI] [PubMed] [Google Scholar]
  23. Pène J., Rousset F., Brière F., Chrétien I., Bonnefoy J. Y., Spits H., Yokota T., Arai N., Arai K., Banchereau J. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6880–6884. doi: 10.1073/pnas.85.18.6880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rousset F., Garcia E., Banchereau J. Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J Exp Med. 1991 Mar 1;173(3):705–710. doi: 10.1084/jem.173.3.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Smith-Ravin J., Spencer J., Beverley P. C., Isaacson P. G. Characterization of two monoclonal antibodies (UCL4D12 and UCL3D3) that discriminate between human mantle zone and marginal zone B cells. Clin Exp Immunol. 1990 Oct;82(1):181–187. doi: 10.1111/j.1365-2249.1990.tb05424.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Szakal A. K., Kosco M. H., Tew J. G. Microanatomy of lymphoid tissue during humoral immune responses: structure function relationships. Annu Rev Immunol. 1989;7:91–109. doi: 10.1146/annurev.iy.07.040189.000515. [DOI] [PubMed] [Google Scholar]
  27. Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]
  28. Thyphronitis G., Tsokos G. C., June C. H., Levine A. D., Finkelman F. D. IgE secretion by Epstein-Barr virus-infected purified human B lymphocytes is stimulated by interleukin 4 and suppressed by interferon gamma. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5580–5584. doi: 10.1073/pnas.86.14.5580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vallé A., Zuber C. E., Defrance T., Djossou O., De Rie M., Banchereau J. Activation of human B lymphocytes through CD40 and interleukin 4. Eur J Immunol. 1989 Aug;19(8):1463–1467. doi: 10.1002/eji.1830190818. [DOI] [PubMed] [Google Scholar]
  30. Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zhang K., Clark E. A., Saxon A. CD40 stimulation provides an IFN-gamma-independent and IL-4-dependent differentiation signal directly to human B cells for IgE production. J Immunol. 1991 Mar 15;146(6):1836–1842. [PubMed] [Google Scholar]
  32. Zubler R. H., Werner-Favre C., Wen L., Sekita K., Straub C. Theoretical and practical aspects of B-cell activation: murine and human systems. Immunol Rev. 1987 Oct;99:281–299. doi: 10.1111/j.1600-065x.1987.tb01181.x. [DOI] [PubMed] [Google Scholar]
  33. de los Toyos J., Jalkanen S., Butcher E. C. Flow cytometric analysis of the Hermes homing-associated antigen on human lymphocyte subsets. Blood. 1989 Aug 1;74(2):751–760. [PubMed] [Google Scholar]

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