The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation
Lijun MengZhenjiang BaiShan HeKazuhiro MochizukiYongnian LiuJanaki PurusheHongxing SunJian WangHideo Yagita∥Shin MineishiHenry C. FungGregory A. YanikRoberto CaricchioXiaoxuan FanLisa CrisalliElizabeth O. HexnerRan ReshefYanyun ZhangYi Zhang
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Notch signaling regulates multiple helper CD4(+) T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease in mice. However, the human counterpart of murine DLL4(+) DCs has yet to be examined. We report the identification of human DLL4(+) DCs and their critical role in regulating Th1 and Th17 differentiation. CD1c(+) DCs and plasmacytoid DCs (pDCs) from the peripheral blood (PB) of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation had a 16-fold more DLL4(+)CD1c(+) DCs than healthy donors. Upon activation of TLR signaling, healthy donor-derived CD1c(+) DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4(+) DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing Ab decreased Notch signaling in T cells stimulated with DLL4(+) DCs, and it reduced the generation of Th1 and Th17 cells. Both NF-κB and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Th1 and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, autoimmunity, and tumor immunity.Keywords:
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Dendritic cells are master regulators of immunity. Immature dendritic cells are essential for maintaining self‐tolerance, while mature dendritic cells initiate a variety of specialized immune responses. Dendritic cell quiescence is often viewed as a default state that requires exogenous stimuli to induce maturation. However, recent studies have identified dendritic cell quiescence factors that actively program dendritic cells to an immature state. In the absence of these factors, dendritic cells spontaneously become immunogenic and can induce autoimmune responses. Herein we discuss two such factors, NF‐κB1 and A20, that preserve dendritic cell immaturity through their regulation of NF‐κB signaling. Loss of either of these factors increases dendritic cell immunogenicity, suggesting that they may be important targets for enhancing dendritic cell–based cancer immunotherapies. Alternatively, defects in molecules critical for maintaining steady‐state DCs may provide novel biomarkers that identify patients who have enhanced natural antitumor immunity or that correlate with better responses to various immunotherapies.
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Dendritic Cell was first found by Steinman in 1973 from mice lymph node. It was named as dendritic cell because of its dendritic morphology. Hepatic dendritic cell was distributed in the base of hepatic portal vein or peri biliarytract or areas nearby the hepatic sinuses.It was a non Kupffer cell.The MHCⅡantigen presented on these cells was stronger than It on Kupffer cells,but it was less than that on other dendritic cells from spleen or bone marrow . Hepatic dendritic cells could proliferate in vitro and migrate to subordinate lymphoid tissue. Hepatic dendritic cells were related with immunological rejection in liver transplantation and other liver diseases.
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General considerations of dendritic cells. Dendritic cells in lymphoid tissues: Their morphology, antigenic profiles and functions. What is an interdigitating cell? What is a follicular dendritic cell? Heterogeneity of dendritic cells. SYMPOSIA. General aspects of dendritic cells in lymphoid tissues. Dendritic cells in situ and in vitro. An immunohistological study on dendritic cells of murine dermis regional lymph node paracortex using monoclonal antibody M1-8 in delayted-type contact hypersensitivity. Distribution and function of dendritic cells in the spleen. Cytogenesis and characteristics of interdigitating cells (IDC). S100+ cells and IDC: Search for IDC-precursors and analysis of differentiation of IDC. The characterization of interdigitating reticulum cells: A comparison between Langerhans cells. Dendritic cells in the thymus. Tolerance induction in the thymus: Role of medullary dendritic cells and possible alternative mechanisms. Dendritic cells in human thymus and thymoma. Characteristics of follicular dendritic cells. An immunohistochemical study on the phenotypic immunostaining pattern of follicular dendritic cells in reactive and pathological lymphoid tissues. Ultrastructure of follicular dendritic cells. Intercellular relations between follicular dendritic cells (FDC) and other cells. Follicular dendritic cells and antigen presentation. Intercellular communications in the lymph follicles. Role of immune complex trapped on follicular dendritic cells (FDC) in the germinal center (GC) in the secondary response. Functional aspects of follicular dendritic cells. Long-term cultivation of human tonsil follicular dendritic cells. Follicular dendritic cell associated proliferation of human lymphocytes in vitro. Immunogenicity of follicular dendritic cell (FDC) associated antigen. Dendritic cells in disease. Abnormal follicular hyperplasia of the persistent generalized lymphadenopathy (PGL) syndrome in HIV-1 infected patients: The results of an immuno-morphologic study. Deterioration of B-cell proliferation correlates with the destruction of follicular dendritic cells in germinal center of HIV-infected lymph nodes. Neoplastic nature and causes of death in Letterer-Siwe disease. Interdigitating cell sarcoma (ITC): Immunocytochemical studies with monoclonal anti-ICS antibodies. Morphology and function of (lymphoid) dendritic cells and related cells. Dendritic cells: Morphofunctional analysis in health and disease. Lymphoid dendritic cells in the reticular framework of RES. Induction of dendritic cells in rat peritoneal cavity after Bacillus Calmetteguerin administration. Maturation, migration and function of dendritic leukocytes after transplantation. Dendritic cells from adenoids of children with otitis media with effusion. A model mouse defective in M-CSF production: Molecular biology and pathology of osteopetrosis mouse (OP/OP). Poster presentations. 20 posters were presented. A full contents list is available from the Publisher on request.
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Les cellules dendritiques sont des cellules du système immunitaire qui engagent les réponses immunitaires. Il existe plusieurs catégories de cellules dendritiques, présentes dans les organes lymphoïdes et les tissus périphériques. Ces dernières années, plusieurs études ont mis en évidence une population de cellules dendritiques qui n’est présente que dans des conditions d’inflammation, d’où le nom de cellules dendritiques inflammatoires. Dans cette revue, nous discutons en quoi les cellules dendritiques inflammatoires diffèrent des macrophages et des autres populations de cellules dendritiques chez la souris. Nous examinons également les travaux récents qui analysent les cellules dendritiques inflammatoires chez l’homme.
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M. Lotze and A. Thomson, Preface. R. Steinman and J. Banchereau, Introduction. Origin of Dendritic Cells: A. Galy, L. Wu, and K. Georgopolous, Hematopoietic Cell Fate and the Development of Dendritic Cells. K. Shortman and L. Wu, Thymic Dendritic Cells. J.W. Young, Cell Fate Development in the Myeloid System. J.G. Tew, Z. Kapasi, D. Qin, and A.K. Szalcal, Origin of Follicular Dendritic Cells. C. Cauz, S. Lebecque, Y.-J. Liu, and J. Banchereau, Development Pathways of Myeloid Dendritic Cells. E. Maraskovsky, B. Pulendran, and K. Shortman, Lymphoid-Related Dendritic Cells. Dendritic Cells in the Periphery: D. Maurer and G. Stingl, Dendritic Cells in the Context of Skin Immunity. A.S. McWilliam, P.A. Stumbles, and P.G. Holt, Dendritic Cells in the Lung. G. MacPherson and L. Lu, Intestinal Dendritic Cells. R.J. Steptoe and A. Thomson, Dendritic Cells in the Liver, Kidney, Heart, and Pancreas. J.M. Austyn, Dendritic cells in Spleen and Lymph Nodes. P. McMenamin and J.V. Forrester, Dendritic Cells in Central Nervous System and Eye and Their Supporting Tissues. Dendritic Cells and Interaction with Other Cells: A. Viola, G. Iezzi, and A. Lanzavecchia, The Role of Dendritic Cells in T Cell Priming: The Importance of Being Professional. B. Chambers and H.-G. Ljunggren, NK Cells. F. Briere, C. Caux, B. Dubois, J. Fayette, S. Vandenabeele, and J. Banchereau, Interaction Between Dendritic Cells and B Lymphocytes. Y. Yamaguchi and M. Ogawa, Dendritic Cells and Cells of the Monocyte/Macrophage Linage. I. Kimber, M. Cumberbatch, R.J. Dearman, and S.C. Knight, Langerhans Cell Migration and Cellular Interactions. A. Larrengina and A. Morelli, Dendritic Cells in the Reproductive Tract. Dendritic Cells in Disease: M. Lotze and R. Jaffe, Cancer. A.J. Demetris, N. Murase, J.J. Fung, and T.E. Starzi, Dendritic Cells in Rejection and Acceptance of Solid Organ Allograft. H.A. Drexage, F.G.A. Delemarre, K. Radosevic, and P.J.M. Leelnan, Dendritic Cells in Autoimmunity. M. Rescigno, M. Rittig, S. Citterio, M. Matsyzak, M. Foti, F. Granucci, M. Martino, U. Fascio, P. Rovere, and P. Ricciardi-Castagnoli, Interaction of Dendritic Cells with Bacteria. R.M. Steinman, A. Granelli-Piperno, K. Tenner-racz, P. Racz, S. Frankel, E. Delgado, R. Ignatius, and M. Pope, Dendritic Cells During Infection with HIV-1 and SIV. A.E. Semper, J.A. Hartley, I.G. Reischl, and S.T. Holgate, Dendritic Cells in Allergy. DC Based Therapies: M. Lotze, H. Farhood, C. Wilson, and W.J. Storkus, Dendritic Cell Therapy of Cancer and HIV Infection. L. Lu, S.J. Khoury, M.H. Sayegh, and A. Thomson, Dendritic Cell Tolerogenicity and Prospects for Dendritic Cell-Based Therapy of Allograft Rejection and Autoimmunity. Techniques and Other Topics in DC Biology: G. Schuler, M. Lutz, A. Bender, B. Thurner, C. Roder, and N. Romani, A Guide to the Isolation and Propagation of Dendritic Cells. S.J. Turley, R.M. Steinmann, I. Mellman, and K. Inaba, Propagation and Culture of Dendritic Cells. G. Clark and D.N.J. Hart, Phenotypic Characterization of Dendritic Cells. M.T. Crowley and D. Lo, Targetted Gene Knockouts: Insights into Dendritic Cell Biology. S. Barrett-Boyes and L.D. Falo, Jr., Mobilization, Migration and Localization of Dendritic Cells. T. Tuting, L. Zitvogel, and Y. Nishioka, Genetic Engineering of Dendritic Cells. J. Gong, D. Avigan, and D. Kufe, Dendritic--Tumor Cell Fusions. M. Cella, M. Salio, D. Scheidegger, A. Engering, J. Pieters, F. Sallusto, and A. Lanzavecchia, Regulation of Antigen Capture, MHC Biosynthesis, and Degradation Optimized Presentation of Infectious Antigens in Maturing Dendritic Cells. G. Girolomani, M. Rescigo, and P.R. Castognoli, Development and Testing of Dendritic Cell Lines. L. Zitvogel, A. Regnault, A. Lozier, G. Raposo, and S. Amigorena, Dendritic Cell--Derived Exosomes: Potent Immunogenic Cell-Free Vaccines. N. Romani, F. Koch, C. Heufler, E. Kampgen, and G. Schuler, Dendritic Cells as Donors and Recipients of Cytokines Signals. M.R. Shurin, C. Esche, A. Lokshin, and M. Lotze, Apoptosis in Dendritic Cells. W.S. Garrett and I. Mellman, Studies of Endocytosis. Appendix. Index.
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Objective: Explore the experiment method for cultured and identified the human dendritic cells in vitro. Simultaneously, the study would provide requirement for DC research.. Methods :Dendritic cells were isolated from human peripheral blood by Ficoll-Hypaque and Precoll, purified by the way of Panning, and cultured in the medium containing GM-CSF (granulocyte/macrophage colony- stimulating factor, 100μg/mL) and IL-4 (interleukin-4, 10μg/mL), and a large of dendritic cells were harvested. Then they were identified by immunohisto- chemical methods. Results: Dendritic cells had dendritic prominency in 3rd day after harvested viewed by scan electromicroscope. After 7th day, dendritic cells larged and had sheet-like veils or lamel-lipodia on the surface of cell. They behaved the positive staining of S-100 protein antibody. Conclusion :Dendritic cells could be isolated from human peripheral blood and cultured a large of dendritic cells in vitro.
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