Abstract
In contrast to adult lymphocytes, neonatal lymphocytes secrete minimal amounts of Ig in response to stimulation with immobilized MAb to CD3. This deficiency could be overcome by the addition of supplemental IL-2, IL-4, or IL-6, resulting in the secretion of all Ig isotypes. There were no major differences in the distribution of Ig isotypes secreted in response to the cytokines alone or in combination. The Ig secreted in response to IL-4 or IL-6 was inhibited by MAb to CD25, suggesting that the effects of IL-4 and IL-6 were dependent on IL-2. Stimulation of neonatal lymphocytes with anti-CD3 was sufficient to induce expression of IL-2 receptors (CD25) on both T and B cells. IL-4 exerted direct effects on neonatal T cells by increasing IL-2 production and promoting IL-6 production by anti-CD3-stimulated neonatal lymphocytes. Antibody to IL-4 or IL-6 did not inhibit Ig secretion in response to IL-2 and antibody to IL-6 did not consistently inhibit Ig secretion in response to IL-4. Finally, in the presence of cyclosporin, anti-CD3-stimulated neonatal lymphocytes secreted Ig only with the combination of IL-2 and IL-4. These results have delineated unique, but not Ig isotype-specific, effects of cytokines in supporting Ig secretion by anti-CD3-stimulated neonatal lymphocytes. Deficient production of these cytokines is likely to contribute to the decreased capacity of neonatal lymphocytes to generate an Ig response.
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Selected References
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- Amoroso K., Lipsky P. E. Frequency of human B cells that differentiate in response to anti-CD3-activated T cells. J Immunol. 1990 Nov 15;145(10):3155–3161. [PubMed] [Google Scholar]
- Andersson U., Andersson J., Lindfors A., Wagner K., Möller G., Heusser C. H. Simultaneous production of interleukin 2, interleukin 4 and interferon-gamma by activated human blood lymphocytes. Eur J Immunol. 1990 Jul;20(7):1591–1596. doi: 10.1002/eji.1830200727. [DOI] [PubMed] [Google Scholar]
- Banchereau J., de Paoli P., Vallé A., Garcia E., Rousset F. Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science. 1991 Jan 4;251(4989):70–72. doi: 10.1126/science.1702555. [DOI] [PubMed] [Google Scholar]
- Baroja M. L., Ceuppens J. L. More exact quantification of interleukin-2 production by addition of anti-Tac monoclonal antibody to cultures of stimulated lymphocytes. J Immunol Methods. 1987 Apr 16;98(2):267–270. doi: 10.1016/0022-1759(87)90014-7. [DOI] [PubMed] [Google Scholar]
- Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
- Clement L. T., Vink P. E., Bradley G. E. Novel immunoregulatory functions of phenotypically distinct subpopulations of CD4+ cells in the human neonate. J Immunol. 1990 Jul 1;145(1):102–108. [PubMed] [Google Scholar]
- Coffman R. L., Ohara J., Bond M. W., Carty J., Zlotnik A., Paul W. E. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol. 1986 Jun 15;136(12):4538–4541. [PubMed] [Google Scholar]
- Defrance T., Aubry J. P., Rousset F., Vanbervliet B., Bonnefoy J. Y., Arai N., Takebe Y., Yokota T., Lee F., Arai K. Human recombinant interleukin 4 induces Fc epsilon receptors (CD23) on normal human B lymphocytes. J Exp Med. 1987 Jun 1;165(6):1459–1467. doi: 10.1084/jem.165.6.1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Del Prete G., Maggi E., Parronchi P., Chrétien I., Tiri A., Macchia D., Ricci M., Banchereau J., De Vries J., Romagnani S. IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol. 1988 Jun 15;140(12):4193–4198. [PubMed] [Google Scholar]
- Del Prete G., Maggi E., Parronchi P., Chrétien I., Tiri A., Macchia D., Ricci M., Banchereau J., De Vries J., Romagnani S. IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol. 1988 Jun 15;140(12):4193–4198. [PubMed] [Google Scholar]
- Ehlers S., Smith K. A. Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory. J Exp Med. 1991 Jan 1;173(1):25–36. doi: 10.1084/jem.173.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ferrante A., Rowan-Kelly B., Beard L. J., Maxwell G. M. An enzyme-linked immunosorbent assay for the quantitation of human IgG subclasses using monoclonal antibodies. J Immunol Methods. 1986 Nov 6;93(2):207–212. doi: 10.1016/0022-1759(86)90190-0. [DOI] [PubMed] [Google Scholar]
- Flanagan J. G., Rabbitts T. H. Arrangement of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing gamma, epsilon and alpha genes. Nature. 1982 Dec 23;300(5894):709–713. doi: 10.1038/300709a0. [DOI] [PubMed] [Google Scholar]
- Galili U., Schlesinger M. The formation of stable E rosettes after neuraminidase treatment of either human peripheral blood lymphocytes or of sheep red blood cells. J Immunol. 1974 May;112(5):1628–1634. [PubMed] [Google Scholar]
- Gathings W. E., Kubagawa H., Cooper M. D. A distinctive pattern of B cell immaturity in perinatal humans. Immunol Rev. 1981;57:107–126. doi: 10.1111/j.1600-065x.1981.tb00444.x. [DOI] [PubMed] [Google Scholar]
- Geppert T. D., Lipsky P. E. Accessory cell independent proliferation of human T4 cells stimulated by immobilized monoclonal antibodies to CD3. J Immunol. 1987 Mar 15;138(6):1660–1666. [PubMed] [Google Scholar]
- Gordon J., Millsum M. J., Guy G. R., Ledbetter J. A. Resting B lymphocytes can be triggered directly through the CDw40 (Bp50) antigen. A comparison with IL-4-mediated signaling. J Immunol. 1988 Mar 1;140(5):1425–1430. [PubMed] [Google Scholar]
- Hayward A. R., Lawton A. R. Induction of plasma cell differentiation of human fetal lymphocytes: evidence for functional immaturity of T and B cells. J Immunol. 1977 Oct;119(4):1213–1217. [PubMed] [Google Scholar]
- Hilbert D. M., Cancro M. P., Scherle P. A., Nordan R. P., Van Snick J., Gerhard W., Rudikoff S. T cell derived IL-6 is differentially required for antigen-specific antibody secretion by primary and secondary B cells. J Immunol. 1989 Dec 15;143(12):4019–4024. [PubMed] [Google Scholar]
- Hirano T., Taga T., Nakano N., Yasukawa K., Kashiwamura S., Shimizu K., Nakajima K., Pyun K. H., Kishimoto T. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci U S A. 1985 Aug;82(16):5490–5494. doi: 10.1073/pnas.82.16.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T., Kashiwamura S., Nakajima K., Koyama K., Iwamatsu A. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986 Nov 6;324(6092):73–76. doi: 10.1038/324073a0. [DOI] [PubMed] [Google Scholar]
- Hirohata S., Jelinek D. F., Lipsky P. E. T cell-dependent activation of B cell proliferation and differentiation by immobilized monoclonal antibodies to CD3. J Immunol. 1988 Jun 1;140(11):3736–3744. [PubMed] [Google Scholar]
- Hirohata S., Lipsky P. E. T cell regulation of human B cell proliferation and differentiation. Regulatory influences of CD45R+ and CD45R- T4 cell subsets. J Immunol. 1989 Apr 15;142(8):2597–2607. [PubMed] [Google Scholar]
- Jabara H. H., Ackerman S. J., Vercelli D., Yokota T., Arai K., Abrams J., Dvorak A. M., Lavigne M. C., Banchereau J., De Vries J. Induction of interleukin-4-dependent IgE synthesis and interleukin-5-dependent eosinophil differentiation by supernatants of a human helper T-cell clone. J Clin Immunol. 1988 Nov;8(6):437–446. doi: 10.1007/BF00916948. [DOI] [PubMed] [Google Scholar]
- 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]
- Jelinek D. F., Lipsky P. E. Inhibitory influence of IL-4 on human B cell responsiveness. J Immunol. 1988 Jul 1;141(1):164–173. [PubMed] [Google Scholar]
- Jelinek D. F., Lipsky P. E. The roles of T cell factors in activation, cell cycle progression, and differentiation of human B cells. J Immunol. 1985 Mar;134(3):1690–1701. [PubMed] [Google Scholar]
- Jelinek D. F., Splawski J. B., Lipsky P. E. Human peripheral blood B lymphocyte subpopulations: functional and phenotypic analysis of surface IgD positive and negative subsets. J Immunol. 1986 Jan;136(1):83–92. [PubMed] [Google Scholar]
- Jelinek D. F., Splawski J. B., Lipsky P. E. The roles of interleukin 2 and interferon-gamma in human B cell activation, growth and differentiation. Eur J Immunol. 1986 Aug;16(8):925–932. doi: 10.1002/eji.1830160809. [DOI] [PubMed] [Google Scholar]
- Kasahara Y., Miyawaki T., Kato K., Kanegane H., Yachie A., Yokoi T., Taniguchi N. Role of interleukin 6 for differential responsiveness of naive and memory CD4+ T cells in CD2-mediated activation. J Exp Med. 1990 Nov 1;172(5):1419–1424. doi: 10.1084/jem.172.5.1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kibler R., Hicks M. J., Wright A. L., Taussig L. M. A comparative analysis of cord blood and adult lymphocytes: interleukin-2 and interferon production, natural killer cell activity, and lymphocyte populations. Diagn Immunol. 1986;4(4):201–208. [PubMed] [Google Scholar]
- Krönke M., Leonard W. J., Depper J. M., Arya S. K., Wong-Staal F., Gallo R. C., Waldmann T. A., Greene W. C. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5214–5218. doi: 10.1073/pnas.81.16.5214. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ledbetter J. A., Shu G., Gallagher M., Clark E. A. Augmentation of normal and malignant B cell proliferation by monoclonal antibody to the B cell-specific antigen BP50 (CDW40). J Immunol. 1987 Feb 1;138(3):788–794. [PubMed] [Google Scholar]
- Matsuzaki N., Saji F., Kameda T., Yoshizaki K., Okada T., Sawai K., Tanizawa O. In vitro and in vivo production of interleukin-6 by fetal mononuclear cells. Clin Immunol Immunopathol. 1990 May;55(2):305–314. doi: 10.1016/0090-1229(90)90106-z. [DOI] [PubMed] [Google Scholar]
- Mitchell L. C., Davis L. S., Lipsky P. E. Promotion of human T lymphocyte proliferation by IL-4. J Immunol. 1989 Mar 1;142(5):1548–1557. [PubMed] [Google Scholar]
- Morell A., Skvaril F., Hitzig W. H., Barandun S. IgG subclasses: development of the serum concentrations in "normal" infants and children. J Pediatr. 1972 Jun;80(6):960–964. doi: 10.1016/s0022-3476(72)80007-6. [DOI] [PubMed] [Google Scholar]
- Morimoto C., Letvin N. L., Distaso J. A., Aldrich W. R., Schlossman S. F. The isolation and characterization of the human suppressor inducer T cell subset. J Immunol. 1985 Mar;134(3):1508–1515. [PubMed] [Google Scholar]
- Muraguchi A., Hirano T., Tang B., Matsuda T., Horii Y., Nakajima K., Kishimoto T. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med. 1988 Feb 1;167(2):332–344. doi: 10.1084/jem.167.2.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oxelius V. A. IgG subclass levels in infancy and childhood. Acta Paediatr Scand. 1979 Jan;68(1):23–27. doi: 10.1111/j.1651-2227.1979.tb04424.x. [DOI] [PubMed] [Google Scholar]
- Powers G. D., Abbas A. K., Miller R. A. Frequencies of IL-2- and IL-4-secreting T cells in naive and antigen-stimulated lymphocyte populations. J Immunol. 1988 May 15;140(10):3352–3357. [PubMed] [Google Scholar]
- 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]
- Renz H., Mazer B. D., Gelfand E. W. Differential inhibition of T and B cell function in IL-4-dependent IgE production by cyclosporin A and methylprednisolone. J Immunol. 1990 Dec 1;145(11):3641–3646. [PubMed] [Google Scholar]
- Salmon M., Kitas G. D., Bacon P. A. Production of lymphokine mRNA by CD45R+ and CD45R- helper T cells from human peripheral blood and by human CD4+ T cell clones. J Immunol. 1989 Aug 1;143(3):907–912. [PubMed] [Google Scholar]
- Sanders M. E., Makgoba M. W., Sharrow S. O., Stephany D., Springer T. A., Young H. A., Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production. J Immunol. 1988 Mar 1;140(5):1401–1407. [PubMed] [Google Scholar]
- Sanders V. M., Fernandez-Botran R., Uhr J. W., Vitetta E. S. Interleukin 4 enhances the ability of antigen-specific B cells to form conjugates with T cells. J Immunol. 1987 Oct 1;139(7):2349–2354. [PubMed] [Google Scholar]
- Smeland E. B., Blomhoff H. K., Funderud S., Shalaby M. R., Espevik T. Interleukin 4 induces selective production of interleukin 6 from normal human B lymphocytes. J Exp Med. 1989 Oct 1;170(4):1463–1468. doi: 10.1084/jem.170.4.1463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Snapper C. M., Finkelman F. D., Paul W. E. Regulation of IgG1 and IgE production by interleukin 4. Immunol Rev. 1988 Feb;102:51–75. doi: 10.1111/j.1600-065x.1988.tb00741.x. [DOI] [PubMed] [Google Scholar]
- Snapper C. M., Paul W. E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987 May 22;236(4804):944–947. doi: 10.1126/science.3107127. [DOI] [PubMed] [Google Scholar]
- Splawski J. B., Jelinek D. F., Lipsky P. E. Delineation of the functional capacity of human neonatal lymphocytes. J Clin Invest. 1991 Feb;87(2):545–553. doi: 10.1172/JCI115029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Splawski J. B., Jelinek D. F., Lipsky P. E. Immunomodulatory role of IL-4 on the secretion of Ig by human B cells. J Immunol. 1989 Mar 1;142(5):1569–1575. [PubMed] [Google Scholar]
- Splawski J. B., McAnally L. M., Lipsky P. E. IL-2 dependence of the promotion of human B cell differentiation by IL-6 (BSF-2). J Immunol. 1990 Jan 15;144(2):562–569. [PubMed] [Google Scholar]
- Thiele D. L., Kurosaka M., Lipsky P. E. Phenotype of the accessory cell necessary for mitogen-stimulated T and B cell responses in human peripheral blood: delineation by its sensitivity to the lysosomotropic agent, L-leucine methyl ester. J Immunol. 1983 Nov;131(5):2282–2290. [PubMed] [Google Scholar]
- Thiele D. L., Lipsky P. E. Modulation of human natural killer cell function by L-leucine methyl ester: monocyte-dependent depletion from human peripheral blood mononuclear cells. J Immunol. 1985 Feb;134(2):786–793. [PubMed] [Google Scholar]
- Uchiyama T., Broder S., Waldmann T. A. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac (+) cells. J Immunol. 1981 Apr;126(4):1393–1397. [PubMed] [Google Scholar]
- Van Damme J., Van Beeumen J., Decock B., Van Snick J., De Ley M., Billiau A. Separation and comparison of two monokines with lymphocyte-activating factor activity: IL-1 beta and hybridoma growth factor (HGF). Identification of leukocyte-derived HGF as IL-6. J Immunol. 1988 Mar 1;140(5):1534–1541. [PubMed] [Google Scholar]
- Wu L. Y., Blanco A., Cooper M. D., Lawton A. R. Ontogeny of B-lymphocyte differentiation induced by pokeweed mitogen. Clin Immunol Immunopathol. 1976 Mar;5(2):208–217. doi: 10.1016/0090-1229(76)90026-x. [DOI] [PubMed] [Google Scholar]