Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Aug 1;184(2):747–752. doi: 10.1084/jem.184.2.747

Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation

PMCID: PMC2192696  PMID: 8760829

Abstract

We investigated the possibility that T helper cells might enhance the stimulatory function of dendritic cells (DCs). We found that ligation of CD40 by CD40L triggers the production of extremely high levels of bioactive IL-12. Other stimuli such as microbial agents, TNF-alpha or LPS are much less effective or not at all. In addition, CD40L is the most potent stimulus in upregulating the expression of ICAM-1, CD80, and CD86 molecules on DCs. These effects of CD40 ligation result in an increased capacity of DCs to trigger proliferative responses and IFN- gamma production by T cells. These findings reveal a new role for CD40- CD40L interaction in regulating DC function and are relevant to design therapeutic strategies using cultured DCs.

Full Text

The Full Text of this article is available as a PDF (1.6 MB).

Selected References

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

  1. Bürk M. R., Mori L., De Libero G. Human V gamma 9-V delta 2 cells are stimulated in a cross-reactive fashion by a variety of phosphorylated metabolites. Eur J Immunol. 1995 Jul;25(7):2052–2058. doi: 10.1002/eji.1830250737. [DOI] [PubMed] [Google Scholar]
  2. D'Andrea A., Ma X., Aste-Amezaga M., Paganin C., Trinchieri G. Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production. J Exp Med. 1995 Feb 1;181(2):537–546. doi: 10.1084/jem.181.2.537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dellabona P., Casorati G., Friedli B., Angman L., Sallusto F., Tunnacliffe A., Roosneek E., Lanzavecchia A. In vivo persistence of expanded clones specific for bacterial antigens within the human T cell receptor alpha/beta CD4-8- subset. J Exp Med. 1993 Jun 1;177(6):1763–1771. doi: 10.1084/jem.177.6.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gately M. K., Warrier R. R., Honasoge S., Carvajal D. M., Faherty D. A., Connaughton S. E., Anderson T. D., Sarmiento U., Hubbard B. R., Murphy M. Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo. Int Immunol. 1994 Jan;6(1):157–167. doi: 10.1093/intimm/6.1.157. [DOI] [PubMed] [Google Scholar]
  5. Grewal I. S., Xu J., Flavell R. A. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature. 1995 Dec 7;378(6557):617–620. doi: 10.1038/378617a0. [DOI] [PubMed] [Google Scholar]
  6. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  7. Inaba K., Metlay J. P., Crowley M. T., Witmer-Pack M., Steinman R. M. Dendritic cells as antigen presenting cells in vivo. Int Rev Immunol. 1990;6(2-3):197–206. doi: 10.3109/08830189009056630. [DOI] [PubMed] [Google Scholar]
  8. Lane P., Burdet C., McConnell F., Lanzavecchia A., Padovan E. CD40 ligand-independent B cell activation revealed by CD40 ligand-deficient T cell clones: evidence for distinct activation requirements for antibody formation and B cell proliferation. Eur J Immunol. 1995 Jun;25(6):1788–1793. doi: 10.1002/eji.1830250646. [DOI] [PubMed] [Google Scholar]
  9. Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature. 1985 Apr 11;314(6011):537–539. doi: 10.1038/314537a0. [DOI] [PubMed] [Google Scholar]
  10. Lanzavecchia A. Identifying strategies for immune intervention. Science. 1993 May 14;260(5110):937–944. doi: 10.1126/science.8493532. [DOI] [PubMed] [Google Scholar]
  11. Macatonia S. E., Hosken N. A., Litton M., Vieira P., Hsieh C. S., Culpepper J. A., Wysocka M., Trinchieri G., Murphy K. M., O'Garra A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995 May 15;154(10):5071–5079. [PubMed] [Google Scholar]
  12. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Murphy E. E., Terres G., Macatonia S. E., Hsieh C. S., Mattson J., Lanier L., Wysocka M., Trinchieri G., Murphy K., O'Garra A. B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med. 1994 Jul 1;180(1):223–231. doi: 10.1084/jem.180.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Roake J. A., Rao A. S., Morris P. J., Larsen C. P., Hankins D. F., Austyn J. M. Dendritic cell loss from nonlymphoid tissues after systemic administration of lipopolysaccharide, tumor necrosis factor, and interleukin 1. J Exp Med. 1995 Jun 1;181(6):2237–2247. doi: 10.1084/jem.181.6.2237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Romani N., Koide S., Crowley M., Witmer-Pack M., Livingstone A. M., Fathman C. G., Inaba K., Steinman R. M. Presentation of exogenous protein antigens by dendritic cells to T cell clones. Intact protein is presented best by immature, epidermal Langerhans cells. J Exp Med. 1989 Mar 1;169(3):1169–1178. doi: 10.1084/jem.169.3.1169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sallusto F., Cella M., Danieli C., Lanzavecchia A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med. 1995 Aug 1;182(2):389–400. doi: 10.1084/jem.182.2.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sallusto F., Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994 Apr 1;179(4):1109–1118. doi: 10.1084/jem.179.4.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Scheicher C., Mehlig M., Dienes H. P., Reske K. Uptake of microparticle-adsorbed protein antigen by bone marrow-derived dendritic cells results in up-regulation of interleukin-1 alpha and interleukin-12 p40/p35 and triggers prolonged, efficient antigen presentation. Eur J Immunol. 1995 Jun;25(6):1566–1572. doi: 10.1002/eji.1830250615. [DOI] [PubMed] [Google Scholar]
  19. Shu U., Kiniwa M., Wu C. Y., Maliszewski C., Vezzio N., Hakimi J., Gately M., Delespesse G. Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction. Eur J Immunol. 1995 Apr;25(4):1125–1128. doi: 10.1002/eji.1830250442. [DOI] [PubMed] [Google Scholar]
  20. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  21. Traunecker A., Oliveri F., Karjalainen K. Myeloma based expression system for production of large mammalian proteins. Trends Biotechnol. 1991 Apr;9(4):109–113. doi: 10.1016/0167-7799(91)90038-j. [DOI] [PubMed] [Google Scholar]
  22. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. doi: 10.1016/0167-5699(93)90230-I. [DOI] [PubMed] [Google Scholar]
  23. Valitutti S., Dessing M., Aktories K., Gallati H., Lanzavecchia A. Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton. J Exp Med. 1995 Feb 1;181(2):577–584. doi: 10.1084/jem.181.2.577. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES