Activation of Dendritic Cells by Surrogate T Cell Interactions Leads to Enhanced Costimulation, Secretion of TH1-Associated Cytokines, and CTL Inductive Capacity
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.
KeywordsDendritic Cell Antigen Present Cell Costimulatory Molecule Dendritic Cell Activation Dendritic Cell Culture
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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.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
- 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
- 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