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T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions

Naturevolume 393, pages480–483 (1998)Cite this article

Abstract

Althoughin vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes1,2, the nature of the ‘help’ provided to CTLs is unknown3. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC)4. An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly5. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions6,7. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity8,9,10,11. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40–CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.

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Figure 1: Cross-priming of E1B-specific CTLs requires CD4+ T-helper cells.
Figure 2: CD40 activation replaces CD4+ helper T cells.
Figure 3: B cells are not essential as cross-priming APCs or for anti-CD40-mediated restoration of cross-priming.
Figure 4: CD40L blockade prevents cross-priming of E1B-specific CTLs.

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References

  1. Simpson, E. & Gordon, R. D. Responsiveness to H-Y antigen. Ir-gene complementation and target cell specificity.Immunol. Rev.35, 59–75 (1997).

    Article  Google Scholar 

  2. Husmann, L. A. & Bevan, M. J. Cooperation between helper T cells and cytotoxic T lymphocyte precursors.Ann. NY Acad. Sci.532, 158–169 (1988).

    Article ADS CAS  Google Scholar 

  3. Bennett, S. R. M., Carbone, F. R., Karamalis, F., Miller, J. F. A. P. & Heath, W. R. Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help.J. Exp. Med.186, 65–70 (1997).

    Article CAS  Google Scholar 

  4. Keene, J. & Forman, J. Helper activity is required for thein vivo generation of cytotoxic T lymphocytes.J. Exp. Med.155, 768–782 (1982).

    Article CAS  Google Scholar 

  5. Guerder, S. & Matzinger, P. Afail-safe mechanism for maintaining self-tolerance.J. Exp. Med.176, 553–564 (1992).

    Article CAS  Google Scholar 

  6. Grewal, I. S., Xu, J. & Flavell, R. A. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand.Nature378, 617–620 (1995).

    Article ADS CAS  Google Scholar 

  7. van Essen, D., Kikutani, H. & Gray, D. CD40 ligand-transduced co-stimulation of T cells in the development of helper function.Nature378, 620–623 (1995).

    Article ADS CAS  Google Scholar 

  8. Koch, F.et al. High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10.J. Exp. Med.184, 741–746 (1996).

    Article CAS  Google Scholar 

  9. Cella, M.et al. 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.J. Exp. Med.184, 747–752 (1996).

    Article CAS  Google Scholar 

  10. Stout, R. D., Suttles, J., Xu, J.-C., Grewal, I. S. & Flavell, R. A. Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice.J. Immunol.156, 8–11 (1996).

    CAS PubMed  Google Scholar 

  11. Kennedy, M. K.et al. Induction of B cell costimulatory function by recombinant murine CD40 ligand.Eur. J. Immunol.24, 116–123 (1994).

    Article CAS  Google Scholar 

  12. Toes, R. E. M.et al. Protective anti-tumor immunity induced by immunization with completely allogeneic tumor cells.Cancer Res.56, 3782–3787 (1996).

    CAS PubMed  Google Scholar 

  13. Bevan, M. J. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic asay.J. Exp. Med.143, 1283–1288 (1976).

    Article CAS  Google Scholar 

  14. Huang, A. Y.et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens.Science264, 961–965 (1994).

    Article ADS CAS  Google Scholar 

  15. Grewal, I. S. & Flavell, R. A. Acentral role of CD40 ligand in the regulation of CD4+ T-cell responses.Immunol. Today17, 410–414 (1996).

    Article CAS  Google Scholar 

  16. Noelle, R. CD40 and its ligand in host defense.Immunity4, 415–419 (1996).

    Article CAS  Google Scholar 

  17. Soong, L.et al. Disruption of CD40–CD40 ligand interactions results in an enhanced susceptibility toLeishmania amazonensis infection.Immunity4, 263–273 (1996).

    Article CAS  Google Scholar 

  18. Mackey, M. F.et al. Protective immunity induced by tumor vaccines requires interactions between CD40 and its ligand, CD154.Cancer Res.57, 2569–2574 (1997).

    CAS PubMed  Google Scholar 

  19. Rolink, A., Melchers, F. & Andersson, J. The SCID but not the RAG-2 gene product is required for the S mu-S epsilon heavy chain class switching.Immunity5, 319–330 (1996).

    Article CAS  Google Scholar 

  20. Grusby, M. J., Johnson, R. S., Papaioannou, V. E. & Glimcher, L. H. Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice.Science253, 1417–1420 (1991).

    Article ADS CAS  Google Scholar 

  21. Shinde, S.et al. CD40L is important for induction of, but not response to, costimulatory activity. ICAM-1 as the second costimulatory molecule rapidly upregulated by CD40L.J. Immunol.157, 2764–2768 (1996).

    CAS PubMed  Google Scholar 

  22. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K. AB cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene.Nature350, 423–426 (1991).

    Article ADS CAS  Google Scholar 

  23. Noelle, R. J.et al. A39-kDa protein on activated T helper cells binds CD40 and transduces the signal for cognate activation of B cells.Proc. Natl Acad. Sci. USA89, 6550–6554 (1992).

    Article ADS CAS  Google Scholar 

  24. Yang, Y. & Wilson, J. M. CD40 ligand-dependent T cell activation: requirement of B7-CD28 signaling through CD40.Science273, 1862–1864 (1996).

    Article ADS CAS  Google Scholar 

  25. Steinman, R. M. The dendritic cell system and its role in immunogenicity.Annu. Rev. Immunol.9, 271–296 (1991).

    Article CAS  Google Scholar 

  26. Mayordomo, J. I.et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity.Nature Med.1, 1297–1302 (1995).

    Article CAS  Google Scholar 

  27. Kurts, C., Kosaka, H., Carbone, F. R., Miller, J. F. A. P. & Heath, W. R. Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8+ T cells.J. Exp. Med.186, 239–245 (1997).

    Article CAS  Google Scholar 

  28. Kast, W. M.et al. Eradication of adenovirus E1-induced tumors by E1a-specific cytotoxic T lymphocytes.Cell59, 603–614 (1989).

    Article CAS  Google Scholar 

  29. Dialynas, D. P.et al. Characterization of the murine T cell surface molecule, designated L3T4, identified by the monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule.J. Immunol.131, 2445–2451 (1983).

    CAS PubMed  Google Scholar 

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Acknowledgements

We thank P. Matzinger for discussions and for providing the B6I–Ab-knockout and µMT mice used in this study; A. Rolink for the FGK45 hybridoma; J. Laman for the purified MR1 antibody; and F. Ossendorp, F. Koning and R. De Vries for critically reading the manuscript and for making suggestions for its improvement. This work was funded by grants from the Dutch Cancer Society and the European Community. R.E.M.T. is a fellow of the Royal Dutch Academy of Arts and Sciences.

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Author notes

  1. Stephen P. Schoenberger

    Present address: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, California, 92121, USA

  2. Stephen P. Schoenberger and Rene E. M. Toes: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunohematology and Blood Bank, University Hospital Leiden, PO Box 9600, 2333 AZ, Leiden, The Netherlands

    Stephen P. Schoenberger, Rene E. M. Toes, Ellen I. H. van der Voort, Rienk Offringa & Cornelis J. M. Melief

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  1. Stephen P. Schoenberger

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Correspondence toStephen P. Schoenberger.

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Schoenberger, S., Toes, R., van der Voort, E.et al. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions.Nature393, 480–483 (1998). https://doi.org/10.1038/31002

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