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.
01 Apr 1994-Journal of Experimental Medicine (Rockefeller University Press)-Vol. 179, Iss: 4, pp 1109-1118
TL;DR: Cultured DCs are as efficient as antigen-specific B cells in presenting tetanus toxoid (TT) to specific T cell clones and their efficiency of antigen presentation can be further enhanced by specific antibodies via FcR- mediated antigen uptake.
Abstract: Using granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 we have established dendritic cell (DC) lines from blood mononuclear cells that maintain the antigen capturing and processing capacity characteristic of immature dendritic cells in vivo. These cells have typical dendritic morphology, express high levels of major histocompatibility complex (MHC) class I and class II molecules, CD1, Fc gamma RII, CD40, B7, CD44, and ICAM-1, and lack CD14. Cultured DCs are highly stimulatory in mixed leukocyte reaction (MLR) and are also capable of triggering cord blood naive T cells. Most strikingly, these DCs are as efficient as antigen-specific B cells in presenting tetanus toxoid (TT) to specific T cell clones. Their efficiency of antigen presentation can be further enhanced by specific antibodies via FcR-mediated antigen uptake. Incubation of these cultured DCs with tumor necrosis factor alpha (TNF-alpha) or soluble CD40 ligand (CD40L) for 24 h results in an increased surface expression of MHC class I and class II molecules, B7, and ICAM-1 and in the appearance of the CD44 exon 9 splice variant (CD44-v9); by contrast, Fc gamma RII is markedly and sometimes completely downregulated. The functional consequences of the short contact with TNF-alpha are in increased T cell stimulatory capacity in MLR, but a 10-fold decrease in presentation of soluble TT and a 100-fold decrease in presentation of TT-immunoglobulin G complexes.
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TL;DR: Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis and the realization that these cells are a powerful tool for manipulating the immune system is realized.
Abstract: B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.
14,532 citations
TL;DR: Dendritic cells are antigen-presenting cells with a unique ability to induce primary immune responses and may be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response.
Abstract: Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.
6,758 citations
TL;DR: Recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues.
Abstract: Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.
4,861 citations
Cites background from "Efficient presentation of soluble a..."
...When cultured, both human monocyte subsets can differentiate into DCs in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4...
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TL;DR: Using a murine adoptive transfer system to probe monocyte homing and differentiation in vivo, two functional subsets among murine blood monocytes are identified: a short-lived CX(3)CR1(lo)CCR2(+)Gr1(+) subset that is actively recruited to inflamed tissues and a CX (3) CR1(hi)CCS1-dependent recruitment to noninflamed tissues.
3,307 citations
Cites background or methods from "Efficient presentation of soluble a..."
...Of note, human CD14 and CD16 sponding human CD16 monocytes are better suited than CD14 monocytes to migrate across endothelialmonocyte subsets can both give rise to DC in vitro (Sal- lusto and Lanzavecchia, 1994; Sanchez-Torres et al., monolayers (Randolph et al., 2002)....
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...…of monocytes into macrophages and their tissue-specific repre-Summary sentatives as well as into DC (Akagawa et al., 1996; Chapuis et al., 1997; Sallusto and Lanzavecchia, 1994;Peripheral blood monocytes are a heterogeneous popZhou and Tedder, 1996; Geissmann et al., 1998; Kiertscherulation of…...
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...This New York, New York 10016 notion is supported by studies with cytokine-driven culture systems that allow in vitro differentiation of monocytes into macrophages and their tissue-specific repreSummary sentatives as well as into DC (Akagawa et al., 1996; Chapuis et al., 1997; Sallusto and Lanzavecchia, 1994; Peripheral blood monocytes are a heterogeneous popZhou and Tedder, 1996; Geissmann et al., 1998; Kiertscher ulation of circulating leukocytes. Using a murine adopand Roth, 1996; Randolph et al., 1998; Schreurs et al., tive transfer system to probe monocyte homing and 1999)....
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TL;DR: It is suggested that several clinical situations, including autoimmunity and certain infectious diseases, can be influenced by the antigen-specific tolerogenic role of DCs.
Abstract: Dendritic cells (DCs) have several functions in innate and adaptive immunity. In addition, there is increasing evidence that DCs in situ induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in the periphery. In the thymus DCs generate tolerance by deleting self-reactive T cells. In peripheral lymphoid organs DCs also induce tolerance to antigens captured by receptors that mediate efficient uptake of proteins and dying cells. Uptake by these receptors leads to the constitutive presentation of antigens on major histocompatibility complex (MHC) class I and II products. In the steady state the targeting of DC antigen capture receptors with low doses of antigens leads to deletion of the corresponding T cells and unresponsiveness to antigenic rechallenge with strong adjuvants. In contrast, if a stimulus for DC maturation is coadministered with the antigen, the mice develop immunity, including interferon-gamma-secreting effector T cells and memory T cells. There is also new evidence that DCs can contribute to the expansion and differentiation of T cells that regulate or suppress other immune T cells. One possibility is that distinct developmental stages and subsets of DCs and T cells can account for the different pathways to peripheral tolerance, such as deletion or suppression. We suggest that several clinical situations, including autoimmunity and certain infectious diseases, can be influenced by the antigen-specific tolerogenic role of DCs.
3,082 citations
Cites background from "Efficient presentation of soluble a..."
...Likewise in vitro, DCs are matured by exposure to lipopolysaccharide (26), inflammatory cytokines including TNF α (27, 28), and CD40 ligation (29–31)....
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References
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TL;DR: Dendritic cells are specialized to mediate several physiologic components of immunogenicity such as the acquisition of antigens in tissues, the migration to lymphoid organs, and the identification and activation of antigen-specific T cells.
Abstract: Dendritic cells are a system of antigen presenting cells that function to initiate several immune responses such as the sensitization of MHC-restricted T cells, the rejection of organ transplants, and the formation of T-dependent antibodies. Dendritic cells are found in many nonlymphoid tissues but can migrate via the afferent lymph or the blood stream to the T-dependent areas of lymphoid organs. In skin, the immunostimulatory function of dendritic cells is enhanced by cytokines, especially GM-CSF. After foreign proteins are administered in situ, dendritic cells are a principal reservoir of immunogen. In vitro studies indicate that dendritic cells only process proteins for a short period of time, when the rate of synthesis of MHC products and content of acidic endocytic vesicles are high. Antigen processing is selectively dampened after a day in culture, but the capacity to stimulate responses to surface bound peptides and mitogens remains strong. Dendritic cells are motile, and efficiently cluster and activate T cells that are specific for stimuli on the cell surface. High levels of MHC class-I and -II products and several adhesins, such as ICAM-1 and LFA-3, likely contribute to these functions. Therefore dendritic cells are specialized to mediate several physiologic components of immunogenicity such as the acquisition of antigens in tissues, the migration to lymphoid organs, and the identification and activation of antigen-specific T cells. The function of these presenting cells in immunologic tolerance is just beginning to be studied.
4,872 citations
"Efficient presentation of soluble a..." refers background in this paper
...It has been shown that LCs form a reservoir of immature DCs that, upon antigenic stimulation, resume their migratory behavior and move to the draining lymph nodes, where they arrive as mature DCs (1, 43)....
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...D endritic cells (DCs) 1 play a critical role in antigen presentation in vivo (1)....
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TL;DR: The methodology for inducing dendritic cell growth that was recently described for mouse blood now has been modified to MHC class II- negative precursors in marrow, and this feature should prove useful for future molecular and clinical studies of this otherwise trace cell type.
Abstract: Antigen-presenting, major histocompatibility complex (MHC) class II-rich dendritic cells are known to arise from bone marrow. However, marrow lacks mature dendritic cells, and substantial numbers of proliferating less-mature cells have yet to be identified. The methodology for inducing dendritic cell growth that was recently described for mouse blood now has been modified to MHC class II-negative precursors in marrow. A key step is to remove the majority of nonadherent, newly formed granulocytes by gentle washes during the first 2-4 d of culture. This leaves behind proliferating clusters that are loosely attached to a more firmly adherent "stroma." At days 4-6 the clusters can be dislodged, isolated by 1-g sedimentation, and upon reculture, large numbers of dendritic cells are released. The latter are readily identified on the basis of their distinct cell shape, ultrastructure, and repertoire of antigens, as detected with a panel of monoclonal antibodies. The dendritic cells express high levels of MHC class II products and act as powerful accessory cells for initiating the mixed leukocyte reaction. Neither the clusters nor mature dendritic cells are generated if macrophage colony-stimulating factor rather than granulocyte/macrophage colony-stimulating factor (GM-CSF) is applied. Therefore, GM-CSF generates all three lineages of myeloid cells (granulocytes, macrophages, and dendritic cells). Since > 5 x 10(6) dendritic cells develop in 1 wk from precursors within the large hind limb bones of a single animal, marrow progenitors can act as a major source of dendritic cells. This feature should prove useful for future molecular and clinical studies of this otherwise trace cell type.
3,852 citations
"Efficient presentation of soluble a..." refers background in this paper
...Proliferating precursors of DCs that can be expanded into DC lines in vitro with GM-CSF are present both in mouse bone marrow (14) and peripheral blood (15)....
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TL;DR: Using a monoclonal antibody raised against a surface glycoprotein of the metastasizing rat pancreatic carcinoma cell line BSp73ASML, cDNA clones have been isolated that encode glycoproteins with partial homology to CD44, a presumed adhesion molecule.
1,703 citations
TL;DR: It is demonstrated that cooperation between GM-CSF and tumour necrosis factor-α (TNF-α) is crucial for the generation of human dendritic/Langerhans cells from CD34+ haematopoietic progenitors.
Abstract: Dendritic cells comprise a system of highly efficient antigen-presenting cells which initiate immune responses such as the sensitization of T cells restricted by major histocompatibility complex molecules, the rejection of organ transplants and the formation of T-cell-dependent antibodies. Dendritic cells are found in many non-lymphoid tissues, such as skin (Langerhans cells) and mucosa, and they migrate after antigen capture through the afferent lymph or the bloodstream to lymphoid organs, where they efficiently present antigen to T cells. Dendritic cells are difficult to isolate and, although they originate from bone marrow their site of maturation and the conditions that direct their growth and differentiation are still poorly characterized. Granulocyte macrophage-colony stimulating factor (GM-CSF) favours the outgrowth of dendritic cells from mouse peripheral blood. Here we extend this finding to man and demonstrate that cooperation between GM-CSF and tumour necrosis factor-alpha (TNF-alpha) is crucial for the generation of human dendritic/Langerhans cells from CD34+ haematopoietic progenitors. The availability of large numbers of these cells should now facilitate the understanding of their role in immunological regulation and disorder.
1,568 citations
TL;DR: It is argued that the requirement for two signals to initiate the adaptive immune response may reflect the evolutionary history of host defences.
1,332 citations