Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Mar 28;92(7):2534–2538. doi: 10.1073/pnas.92.7.2534

IgE receptor-positive non-B/non-T cells dominate the production of interleukin 4 and interleukin 6 in immunized mice.

I Aoki 1, C Kinzer 1, A Shirai 1, W E Paul 1, D M Klinman 1
PMCID: PMC42252  PMID: 7708680

Abstract

The phenotype and antigenic specificity of cells secreting interleukin (IL) 4, IL-6, and interferon gamma was studied in mice during primary and secondary immune responses. T lymphocytes were the major source of interferon gamma, whereas non-B/non-T cells were the dominant source of IL-4 and IL-6 in the spleens of immunized animals. Cytokine-secreting non-B/non-T cells expressed surface receptors for IgE and/or IgG types II/III. Exposing these cells to antigen-specific IgE or IgG in vivo (or in vitro) "armed" them to release IL-4 and IL-6 upon subsequent antigenic challenge. These findings suggest that non-B/non-T cells may represent the "natural immunity" analogue of CD4+ T helper type 2 cells and participate in a positive feedback loop involved in the perpetuation of T helper type 2 cell responses.

Full text

PDF
2534

Images in this article

2537Fig. 3
on p.2537

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
  2. Balkwill F. R., Burke F. The cytokine network. Immunol Today. 1989 Sep;10(9):299–304. doi: 10.1016/0167-5699(89)90085-6. [DOI] [PubMed] [Google Scholar]
  3. Ben-Sasson S. Z., Le Gros G., Conrad D. H., Finkelman F. D., Paul W. E. Cross-linking Fc receptors stimulate splenic non-B, non-T cells to secrete interleukin 4 and other lymphokines. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1421–1425. doi: 10.1073/pnas.87.4.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brown M. A., Pierce J. H., Watson C. J., Falco J., Ihle J. N., Paul W. E. B cell stimulatory factor-1/interleukin-4 mRNA is expressed by normal and transformed mast cells. Cell. 1987 Aug 28;50(5):809–818. doi: 10.1016/0092-8674(87)90339-4. [DOI] [PubMed] [Google Scholar]
  5. Brunner T., Heusser C. H., Dahinden C. A. Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation. J Exp Med. 1993 Mar 1;177(3):605–611. doi: 10.1084/jem.177.3.605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cicco N. A., Lindemann A., Content J., Vandenbussche P., Lübbert M., Gauss J., Mertelsmann R., Herrmann F. Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha. Blood. 1990 May 15;75(10):2049–2052. [PubMed] [Google Scholar]
  7. Conrad D. H., Ben-Sasson S. Z., Le Gros G., Finkelman F. D., Paul W. E. Infection with Nippostrongylus brasiliensis or injection of anti-IgD antibodies markedly enhances Fc-receptor-mediated interleukin 4 production by non-B, non-T cells. J Exp Med. 1990 May 1;171(5):1497–1508. doi: 10.1084/jem.171.5.1497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cuturi M. C., Anegón I., Sherman F., Loudon R., Clark S. C., Perussia B., Trinchieri G. Production of hematopoietic colony-stimulating factors by human natural killer cells. J Exp Med. 1989 Feb 1;169(2):569–583. doi: 10.1084/jem.169.2.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Czerkinsky C., Andersson G., Ekre H. P., Nilsson L. A., Klareskog L., Ouchterlony O. Reverse ELISPOT assay for clonal analysis of cytokine production. I. Enumeration of gamma-interferon-secreting cells. J Immunol Methods. 1988 May 25;110(1):29–36. doi: 10.1016/0022-1759(88)90079-8. [DOI] [PubMed] [Google Scholar]
  10. Else K. J., Finkelman F. D., Maliszewski C. R., Grencis R. K. Cytokine-mediated regulation of chronic intestinal helminth infection. J Exp Med. 1994 Jan 1;179(1):347–351. doi: 10.1084/jem.179.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Handa K., Suzuki R., Matsui H., Shimizu Y., Kumagai K. Natural killer (NK) cells as a responder to interleukin 2 (IL 2). II. IL 2-induced interferon gamma production. J Immunol. 1983 Feb;130(2):988–992. [PubMed] [Google Scholar]
  12. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heinzel F. P., Sadick M. D., Mutha S. S., Locksley R. M. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011–7015. doi: 10.1073/pnas.88.16.7011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Klinman D. M., Haynes B. F., Conover J. Activation of interleukin 4- and interleukin 6-secreting cells by HIV-specific synthetic peptides. AIDS Res Hum Retroviruses. 1995 Jan;11(1):97–105. doi: 10.1089/aid.1995.11.97. [DOI] [PubMed] [Google Scholar]
  15. Kupfer A., Swain S. L., Singer S. J. The specific direct interaction of helper T cells and antigen-presenting B cells. II. Reorientation of the microtubule organizing center and reorganization of the membrane-associated cytoskeleton inside the bound helper T cells. J Exp Med. 1987 Jun 1;165(6):1565–1580. doi: 10.1084/jem.165.6.1565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Le Gros G., Ben-Sasson S. Z., Conrad D. H., Clark-Lewis I., Finkelman F. D., Plaut M., Paul W. E. IL-3 promotes production of IL-4 by splenic non-B, non-T cells in response to Fc receptor cross-linkage. J Immunol. 1990 Oct 15;145(8):2500–2506. [PubMed] [Google Scholar]
  17. Moore K. W., Vieira P., Fiorentino D. F., Trounstine M. L., Khan T. A., Mosmann T. R. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science. 1990 Jun 8;248(4960):1230–1234. doi: 10.1126/science.2161559. [DOI] [PubMed] [Google Scholar]
  18. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  19. O'Garra A., Barbis D., Harada N., Lee F., Howard M. Constitutive production of lymphokines by cloned murine B-cell lymphomas--CH12 B lymphoma produces interleukin-4. J Mol Cell Immunol. 1989;4(3):149–159. [PubMed] [Google Scholar]
  20. Parronchi P., De Carli M., Manetti R., Simonelli C., Sampognaro S., Piccinni M. P., Macchia D., Maggi E., Del Prete G., Romagnani S. IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. J Immunol. 1992 Nov 1;149(9):2977–2983. [PubMed] [Google Scholar]
  21. Paul W. E. Pleiotropy and redundancy: T cell-derived lymphokines in the immune response. Cell. 1989 May 19;57(4):521–524. doi: 10.1016/0092-8674(89)90121-9. [DOI] [PubMed] [Google Scholar]
  22. Paul W. E., Seder R. A., Plaut M. Lymphokine and cytokine production by Fc epsilon RI+ cells. Adv Immunol. 1993;53:1–29. [PubMed] [Google Scholar]
  23. Piccinni M. P., Macchia D., Parronchi P., Giudizi M. G., Bani D., Alterini R., Grossi A., Ricci M., Maggi E., Romagnani S. Human bone marrow non-B, non-T cells produce interleukin 4 in response to cross-linkage of Fc epsilon and Fc gamma receptors. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8656–8660. doi: 10.1073/pnas.88.19.8656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Poo W. J., Conrad L., Janeway C. A., Jr Receptor-directed focusing of lymphokine release by helper T cells. Nature. 1988 Mar 24;332(6162):378–380. doi: 10.1038/332378a0. [DOI] [PubMed] [Google Scholar]
  25. Schleimer R. P., Sterbinsky S. A., Kaiser J., Bickel C. A., Klunk D. A., Tomioka K., Newman W., Luscinskas F. W., Gimbrone M. A., Jr, McIntyre B. W. IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1. J Immunol. 1992 Feb 15;148(4):1086–1092. [PubMed] [Google Scholar]
  26. Seder R. A., Paul W. E., Davis M. M., Fazekas de St Groth B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 1992 Oct 1;176(4):1091–1098. doi: 10.1084/jem.176.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Seder R. A., Paul W. E., Dvorak A. M., Sharkis S. J., Kagey-Sobotka A., Niv Y., Finkelman F. D., Barbieri S. A., Galli S. J., Plaut M. Mouse splenic and bone marrow cell populations that express high-affinity Fc epsilon receptors and produce interleukin 4 are highly enriched in basophils. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2835–2839. doi: 10.1073/pnas.88.7.2835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shirai A., Holmes K., Klinman D. Detection and quantitation of cells secreting IL-6 under physiologic conditions in BALB/c mice. J Immunol. 1993 Feb 1;150(3):793–799. [PubMed] [Google Scholar]
  29. Shirai A., Sierra V., Kelly C. I., Klinman D. M. Individual cells simultaneously produce both IL-4 and IL-6 in vivo. Cytokine. 1994 May;6(3):329–336. doi: 10.1016/1043-4666(94)90030-2. [DOI] [PubMed] [Google Scholar]
  30. Shirai A., Sierra V., Kelly C. I., Klinman D. M. Individual cells simultaneously produce both IL-4 and IL-6 in vivo. Cytokine. 1994 May;6(3):329–336. doi: 10.1016/1043-4666(94)90030-2. [DOI] [PubMed] [Google Scholar]
  31. Tanaka T., Hu-Li J., Seder R. A., Fazekas de St Groth B., Paul W. E. Interleukin 4 suppresses interleukin 2 and interferon gamma production by naive T cells stimulated by accessory cell-dependent receptor engagement. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5914–5918. doi: 10.1073/pnas.90.13.5914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Terebuh P. D., Otterness I. G., Strieter R. M., Lincoln P. M., Danforth J. M., Kunkel S. L., Chensue S. W. Biologic and immunohistochemical analysis of interleukin-6 expression in vivo. Constitutive and induced expression in murine polymorphonuclear and mononuclear phagocytes. Am J Pathol. 1992 Mar;140(3):649–657. [PMC free article] [PubMed] [Google Scholar]
  33. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278. doi: 10.1146/annurev.iy.08.040190.001345. [DOI] [PubMed] [Google Scholar]
  34. Williams M. E., Kullberg M. C., Barbieri S., Caspar P., Berzofsky J. A., Seder R. A., Sher A. Fc epsilon receptor-positive cells are a major source of antigen-induced interleukin-4 in spleens of mice infected with Schistosoma mansoni. Eur J Immunol. 1993 Aug;23(8):1910–1916. doi: 10.1002/eji.1830230827. [DOI] [PubMed] [Google Scholar]
  35. Woloski B. M., Fuller G. M. Identification and partial characterization of hepatocyte-stimulating factor from leukemia cell lines: comparison with interleukin 1. Proc Natl Acad Sci U S A. 1985 Mar;82(5):1443–1447. doi: 10.1073/pnas.82.5.1443. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES