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      Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo

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          Abstract

          Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon γ and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.

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          Most cited references 48

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

          Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. 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). 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 directly. 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 functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. 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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            Cd8+ but Not Cd8− Dendritic Cells Cross-Prime Cytotoxic T Cells in Vivo

            Bone marrow–derived antigen-presenting cells (APCs) take up cell-associated antigens and present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells in a process referred to as cross-priming. Cross-priming is essential for the induction of CD8+ T cell responses directed towards antigens not expressed in professional APCs. Although in vitro experiments have shown that dendritic cells (DCs) and macrophages are capable of presenting exogenous antigens in association with MHC class I, the cross-presenting cell in vivo has not been identified. We have isolated splenic DCs after in vivo priming with ovalbumin-loaded β2-microglobulin–deficient splenocytes and show that they indeed present cell-associated antigens in the context of MHC class I molecules. This process is transporter associated with antigen presentation (TAP) dependent, suggesting an endosome to cytosol transport. To determine whether a specific subset of splenic DCs is involved in this cross-presentation, we negatively and positively selected for CD8− and CD8+ DCs. Only the CD8+, and not the CD8−, DC subset demonstrates cross-priming ability. FACS® studies after injection of splenocytes loaded with fluorescent beads showed that 1 and 0.6% of the CD8+ and the CD8− DC subsets, respectively, had one or more associated beads. These results indicate that CD8+ DCs play an important role in the generation of cytotoxic T lymphocyte responses specific for cell-associated antigens.
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              Innate immune recognition: mechanisms and pathways.

              The innate immune system is an evolutionarily ancient form of host defense found in most multicellular organisms. Inducible responses of the innate immune system are triggered upon pathogen recognition by a set of pattern recognition receptors. These receptors recognize conserved molecular patterns shared by large groups of microorganisms. Recognition of these patterns allows the innate immune system not only to detect the presence of an infectious microbe, but also to determine the type of the infecting pathogen. Pattern recognition receptors activate conserved host defense signaling pathways that control the expression of a variety of immune response genes.
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                Author and article information

                Contributors
                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                17 September 2001
                : 194
                : 6
                : 769-780
                Affiliations
                [a ]Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021
                [b ]Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021
                [c ]Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
                [d ]Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021
                [e ]Laboratory of Immunobiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan
                Article
                011111
                2195961
                11560993
                © 2001 The Rockefeller University Press
                Categories
                Original Article

                Medicine

                peripheral t cell tolerance, dec 205, antigen delivery, dendritic cells, cd40

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