Activation of Dendritic Cells by Surrogate T Cell Interactions Leads to Enhanced Costimulation, Secretion of TH1-Associated Cytokines, and CTL Inductive Capacity

  • Cara C. Wilson
  • Thomas Tueting
  • Debora Ma
  • Cathy Haluszczak
  • Michael Lotze
  • Walter Storkus
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 417)


Dendritic cells (DC), as professional antigen presenting cells (APC), have the capacity to capture antigen and migrate to lymphoid organs, where antigen presentation to and priming of naive T cells takes place (reviewed in 1). It is currently believed that effective induction of antigen-specific T cell responses requires a dynamic dialogue of multiple, sequential interactions between the DC as APC and a given T cell clone in order to prime the cell for expansion and effector function. The first interaction (signal 1) is felt to involve the MHC I/II-peptide on APC with the T cell receptor (TCR) on the effector lymphocyte, with a second signal being the costimulatory interaction between CD80 (B7.1)/CD86(B7.2) on DC with CD28 on the T cell. Signals 1 and 2 combine to activate the T cell, upregulating the expression of CD4OL which can interact with DC-expressed CD40 (reviewed in 2). This DC-T cell interaction results in the generation of an antigen-specific T cell responses. The ability of DC to prime naive T cells has been attributed to several factors, most notably the high levels of expression of MHC and costimulatory molecules such as B7.1 and B7.2. It has also been shown that DC are capable of producing several cytokines, among them IL-12, a cytokine critical for the development of Thl responses (3,4). Recently, ligation of CD40 on both human (5) and murine (6) DC has been reported to result in the upregulation of costimulatory molecules and the induction of IL-12. These findings suggest that the interaction of T cells with DC result in signals to DC which are critical for induction of the cellular immune response. Whereas many of the signals required by T cells for activation and proliferation have been described, the signaling requirements for optimal DC activation remain poorly defined.


Dendritic Cell Antigen Present Cell Costimulatory Molecule Dendritic Cell Activation Dendritic Cell Culture 
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  1. 1.
    Caux C, Liu YJ, Banchereau J. Recent Advances in the Study of Dendritic Cells and Follicular Dendritic Cells. Immunol Today. 1995; 16: 2–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Grewal IS, Flavell RA. A Central Role of CD40 Ligand in the Regulation of CD4+ T-cell Responses. Immunol Today. 1996; 17: 410–414.PubMedCrossRefGoogle Scholar
  3. 3.
    Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh CS, Culpepper JA, Wysocka M, Trinchieri G, Murphy KM, O’Garra A. Dendritic Cells Produce IL-12 and Direct the Development of Thl Cells from Naive CD4+ T cells. J Immunol 1995; 154: 5071–5079.PubMedGoogle Scholar
  4. 4.
    Scheicher C, Mehling M, Dienes HP, Reske K. Uptake of Microparticle-absorbed Protein Antigen by Bone Marrow Dendritic Cells Results in Upregulation of Interleukin-la and Interleukin-12 p40/p35 and Triggers Prolonged, Efficient Antigen Presentation. Eur J Immunol 1995; 25: 1566–1572.PubMedCrossRefGoogle Scholar
  5. 5.
    Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. Ligation of CD40 on Dendritic Cells Triggers Production of High Levels of Interleukin-l2 and Enhances T Cell Stimulatory Capacity: T-T Help via APC Activation. J Exp Med 1996; 184: 747–752.PubMedCrossRefGoogle Scholar
  6. 6.
    Koch F, Stanzl U, Jennewein P, Janke K, Heutler C, Kämpgen, Romani N, Schuler G. High Level IL-12 Production by Murine Dendritic Cells: Upregulation via MHC Class 11 and CD40 Molecules and Down-regulation by IL-4 and IL-10.J Exp Med 1996, 184: 741–746.Google Scholar
  7. 7.
    Sallsto 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; 179: 1109–1118.CrossRefGoogle Scholar
  8. 8.
    Kiertscher SM, Roth MD. Human CD14+ leukocytes Acquire the Phenotype and Function of Antigen-Presenting Dendritic Cells when Cultured in GM-CSF and II-4. J Leuk Biol. 1996; 59: 208–218.Google Scholar
  9. 9.
    Storkus WJ, Alexander J, Payne JA, Dawson JR, Cresswell P. Reversal of NK susceptibility in target cells expressing transfected class I HLA genes. Proc Natl Acad Sci USA 1989, 86: 2361–2367.PubMedCrossRefGoogle Scholar
  10. 10.
    Jung T, Schauer U, Heusser C, Neumann C, Reiger C. Detection of intracellular cytokines by flow cytometry. J Immunol Methods 1993, 159: 197–207.PubMedCrossRefGoogle Scholar
  11. 11.
    Steinman RM. The Dendritic Cell System and Its Role in Immunogenicity. Annu Rev Immunol 1991; 9: 271–296.PubMedCrossRefGoogle Scholar
  12. 12.
    Young.1W, Inaba K. Dendritic Cells as Adjuvants for Class 1 Major Histocompatibility Complex-Restricted Antitumor Immunity. J Exp Med 1996; 183: 7–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Mayordomo Jl, Zorina T, Storkus WJ, Zilvogel L, Celluzzi C, Falo LD, Melicf CJ. lldstad ST, Kast WM, DeLeo A. Lotze MT. Bone Marrow Derived Dendritic Cells Pulsed with Synthetic Tumor Peptides Elicit Protective and Therapeutic Anti-tumor Immunity. Nature Med 1995; 1: 1297–1302.Google Scholar
  14. 14.
    Manetti R, Parronchi P, Guidizi MG, Piccinini MP, Maggi E, Trinchieri G, Romagnani S. Natural Kille Cell Stimulatory Factor (interleukin 12 [IL-12]) Induces T Helper Type 1 (thl)-specific Immune Responses and Inhibits the Development of IL4-producing Th Cells. J Exp Med 1993; 177: 1199–1204.PubMedCrossRefGoogle Scholar
  15. 15.
    Trinchieri G. Interleukin-12 and its Role in the Generation ofThl Cells. Immunol Today 1993; 14: 335–338.PubMedCrossRefGoogle Scholar
  16. 16.
    Heufler C, Koch F. Stanzl U, Topar G. Wysocka M, Trinchieri G, Enk A, Steinman RM, Romani N, Schuler G. Interleukin-12 is produced by dendritic cells and mediates TH I development as well as Interferon-gamma production by TIII cells. Fur J Immunol 1996. 26: 659–668.Google Scholar
  17. 17.
    Ferbas JJ, Toso JE, Logar AJ. Navratil JS, Rinaldo CR. CD4+ Blood Dendritic Cells are Potent Producers of IFN-u in Response to In Vitro HIV-1 Infection. J Immunol 1994; 152: 4649–4662.PubMedGoogle Scholar
  18. 18.
    Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon Alpha Increases the Frequency of Interferon Gamma-producing Human CD4+ T Cells. J Exp Med. 1993; 178: 1655–1663.PubMedCrossRefGoogle Scholar
  19. 19.
    Hokin VK, Kohno K, Minowada J. Natural Human Interferon-a Augments Interleukin-2 Production by a Direct Action on the Activated IL-2-producing T Cells. J Interferon Res 1991; 11: 319.CrossRefGoogle Scholar
  20. 20.
    Schandene I., Del Prete GF, Cogan E, Stordeur P, Crusiaux A. Kennes B, Romagnani S, Goldman M. Recombinant Interferon-alpha Selectively Inhibits the Production of Interleukin-5 by Human CD4+ T Cells. J Clin Invest 1996; 97: 309–315.PubMedCrossRefGoogle Scholar
  21. 21.
    Manetti R, Annunziato F, Tomasevic L, Gianno V, Parronchi P, Romagnani S, Maggi E. Polyinosinic Acid: Polycytidylic Acid Promotes T helper Type 1-Specific Immune Responses by Stimulating Macrophage Production of Interferon-alpha and Interleukin-12. Eur J Immunol 1995; 25: 2656–2660.PubMedCrossRefGoogle Scholar
  22. 22.
    Tough DF, Borrow P, Sprent J. Induction of Bystander T cell Proliferation by Viruses and Type 1 Interferon in vivo. Science 1996; 272: 1947.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Cara C. Wilson
    • 1
  • Thomas Tueting
    • 2
  • Debora Ma
    • 2
  • Cathy Haluszczak
    • 2
  • Michael Lotze
    • 2
  • Walter Storkus
    • 2
  1. 1.Department of MedicineUniversity of Pittsburgh Medical Center and the University of Pittsburgh Cancer InstitutePittsburghUSA
  2. 2.Department of SurgeryUniversity of Pittsburgh Medical Center and the University of Pittsburgh Cancer InstitutePittsburghUSA

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