Journal articles on the topic 'Regulatory DC'
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1
Via, Steve H. "DC Beat -- Drinking Water Regulatory Priorities." Journal - American Water Works Association 109 (May 1, 2017): 88–91. http://dx.doi.org/10.5942/jawwa.2017.109.0067.
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Barchet, Winfried, Jeffrey D. Price, Marina Cella, Marco Colonna, Sandra K. MacMillan, J. Perren Cobb, Paul A. Thompson, Kenneth M. Murphy, John P. Atkinson, and Claudia Kemper. "Complement-induced regulatory T cells suppress T-cell responses but allow for dendritic-cell maturation." Blood 107, no. 4 (February 15, 2006): 1497–504. http://dx.doi.org/10.1182/blood-2005-07-2951.
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Concurrent activation of the T-cell receptor (TCR) and complement regulator CD46 on human CD4+ T lymphocytes induces Tr1-like regulatory T cells that suppress through IL-10 secretion bystander T-cell proliferation. Here we show that, despite their IL-10 production, CD46-induced T-regulatory T cells (Tregs) do not suppress the activation/maturation of dendritic cells (DCs). DC maturation by complement/CD46-induced Tregs is mediated through simultaneous secretion of GM-CSF and soluble CD40L, factors favoring DC differentiation and reversing inhibitory effects of IL-10. Thus, CD46-induced Tregs produce a distinct cytokine profile that inhibits T-cell responses but leaves DC activation unimpaired. Such “DC-sparing” Tregs could be desirable at host/environment interfaces such as the gastrointestinal tract where their specific cytokine profile provides a mechanism that ensures unresponsiveness to commensal bacteria while maintaining reactivity to invading pathogens.
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Diao, Jun, Anastassia Mikhailova, Michael Tang, Hongtao Gu, Jun Zhao, and Mark S. Cattral. "Immunostimulatory conventional dendritic cells evolve into regulatory macrophage-like cells." Blood 119, no. 21 (May 24, 2012): 4919–27. http://dx.doi.org/10.1182/blood-2011-11-392894.
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Abstract Dendritic cell (DC) homeostasis in peripheral tissues reflect a balance between DC generation, migration, and death. The current model of DC ontogeny indicates that pre-cDCs are committed to become terminal conventional DCs (cDCs). Here, we report the unexpected finding that proliferating immunostimulatory CD11c+ MHC class II+ cDCs derived from pre-cDCs can lose their DC identity and generate progeny that exhibit morphologic, phenotypic, and functional characteristics of regulatory macrophages. DC-derived–macrophages (DC-d-Ms) potently suppress T-cell responses through the production of immunosuppressive molecules including nitric oxide, arginase, and IL-10. Relative deficiency of granulocyte-macrophage colony stimulating factor (GM-CSF) provided a permissive signal for DC-d-M generation. Using a transgenic mouse model that allows tracking of CD11c+ cells in vivo, we found that DC-d-M development occurs commonly in cancer, but not in lymphoid or nonlymphoid tissues under steady-state conditions. We propose that this developmental pathway serves as an alternative mechanism of regulating DC homeostasis during inflammatory processes.
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Poncini, Carolina Verónica, Catalina Dirney Alba Soto, Estela Batalla, Maria Elisa Solana, and Stella Maris González Cappa. "Trypanosoma cruzi Induces Regulatory Dendritic Cells In Vitro." Infection and Immunity 76, no. 6 (March 17, 2008): 2633–41. http://dx.doi.org/10.1128/iai.01298-07.
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ABSTRACT A main feature of acute infection with Trypanosoma cruzi is the presence of immunological disorders. A previous study demonstrated that acute infection with the virulent RA strain downregulates the expression of major histocompatibility complex class II (MHC-II) on antigen-presenting cells and impairs the T-cell stimulatory capacity of splenic dendritic cells (DC). In the present work, we assessed the ability of trypomastigotes (Tp) to modulate the differentiation stage and functionality of bone marrow-derived DC in vitro. We observed that the Tp stage of T. cruzi failed to activate DC, which preserved their low expression of MHC-II and costimulatory molecules, as well as their endocytic activity. We also show that Tp induced transforming growth factor β (TGF-β) secretion by DC and enhanced the gap between interleukin-10 (IL-10) and IL-12p70 production, showing a higher IL-10/IL-12p70 ratio upon lipopolysaccharide (LPS) treatment. In addition, we observed that Tp prevented DC full activation induced by LPS, thereby downregulating their MHC-II surface expression and inhibiting their capacity to stimulate lymphocyte proliferation. In vitro IL-10 neutralization during the differentiation process of DC with Tp+LPS showed a reversion of their inhibitory effect during mixed lymphocyte reaction. In contrast, only simultaneous neutralization of IL-10 and TGF-β, after DC differentiation, was involved in the partial restitution of lymphocyte proliferation. Since both TGF-β and IL-10 are immunosuppressive cytokines essential in the modulation of the immune response and important in the induction of tolerance, our results suggest for the first time that Tp are responsible for the generation of regulatory DC in vitro.
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Johnson, Jarrod S., Nicholas De Veaux, Alexander W. Rives, Xavier Lahaye, Sasha Y. Lucas, Brieuc Pérot, Marine Luka, et al. "A comprehensive map of the human dendritic cell HIV-response transcriptional network." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 75.11. http://dx.doi.org/10.4049/jimmunol.202.supp.75.11.
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Abstract Transcriptional programming of the innate immune response is pivotal for host protection. However, the transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During infection with HIV-1, human dendritic cells (DCs) can detect the virus through an innate sensing pathway leading to antiviral type I interferon and DC maturation. Here, we have developed an iterative experimental and computational approach to map the innate response circuitry during HIV-1 infection. By integrating genome-wide chromatin accessibility with expression kinetics, we have inferred a gene regulatory network that links 542 transcription factors (TFs) with 21,862 target genes. Through genetic perturbation and drug treatments we identify PRDM1 and RARA as essential regulators of the interferon response and DC maturation, respectively. Our work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting the complexity and cooperativity in the regulatory circuit controlling the DC response to HIV-1 infection.
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Lipscomb, Michael W., Jennifer L. Taylor, Cristina J. Goldbach, Simon C. Watkins, Amy K. Wesa, and Walter J. Storkus. "DC expressing transgene Foxp3 are regulatory APC." European Journal of Immunology 40, no. 2 (February 2010): 480–93. http://dx.doi.org/10.1002/eji.200939667.
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Huang, Gonghua, Yanyan Wang, and Hongbo Chi. "TAK1-dependent checkpoint in dendritic cell survival promotes immune homeostasis and function (111.53)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 111.53. http://dx.doi.org/10.4049/jimmunol.188.supp.111.53.
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Abstract Homeostatic control of dendritic cell (DC) survival is crucial for adaptive immunity, but the molecular mechanism is not well defined. Moreover, how DCs influence immune homeostasis under steady state remains unclear. Combining DC-specific and inducible deletion systems, we report that the kinase TAK1 is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c+ cells induced markedly elevated apoptosis, leading to the depletion of DC populations, especially the CD8+ and CD103+ DC subsets in lymphoid and non-lymphoid tissues, respectively. TAK1 also contributed to DC development by promoting the generation of DC precursors. Pro-survival signals from Toll-like receptors, CD40 and RANK are integrated by TAK1 in DCs, which in turn mediated activation of downstream NFκ-B and AKT-Foxo pathways and established a gene-expression program. TAK1 deficiency in DCs caused a myeloid proliferative disorder characterized by expansion of neutrophils and inflammatory monocytes, disrupted T cell homeostasis, and prevented effective T cell priming and generation of regulatory T cells. Moreover, TAK1 signaling in DCs was required to prevent myeloid proliferation even in the absence of lymphocytes, indicating a previously unappreciated regulatory mechanism of DC-mediated control of myeloid cell-dependent inflammation. Therefore, TAK1 orchestrates a pro-survival checkpoint in DCs that affects the homeostasis and function of the immune system.
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Rosborough, Brian, Dàlia Raïch-Regué, Benjamin Matta, Keunwook Lee, Mark Boothby, Heth Turnquist, and Angus Thomson. "Rapamycin-resistant mTORC1 restrains dendritic cell B7-H1 expression that requires IL-1β to enhance regulatory T cell induction (P1349)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 63.27. http://dx.doi.org/10.4049/jimmunol.190.supp.63.27.
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Abstract Introduction: The mammalian Target of Rapamycin (mTOR) is a central regulator of dendritic cell (DC) function that performs the catalytic activity of mTOR complex (mTORC)1 and 2. mTORC2 functions independently from mTORC1 and is resistant to inhibition by rapamycin (RAPA); however, mTORC1 has both RAPA-sensitive and -resistant outputs. Our goal was to ascertain the role of RAPA-resistant mTOR in DC. Methods: WT C57BL/6 or B7-H1-/- bone marrow-derived DC were generated with the addition of RAPA or ATP-competitive mTOR inhibitor, which blocks all mTOR signaling. DC lacking rictor, an mTORC2-specific subunit, were generated from conditional rictor KO mice. DC induction of regulatory T cells (Treg) was determined in MLR, using BALB/c CD4+CD25- T cell responders. Results and Conclusion: RAPA and mTORC2 deletion reduced DC B7-H1 expression, but ATP-competitive mTOR inhibitors enhanced B7-H1 expression. Augmented B7-H1 expression was blocked by STAT3 inhibition and correlated with reduced expression of the STAT3 negative regulator, SOCS3. DC exposed to ATP-competitive mTOR inhibitors increased Treg induction, which was dependent on DC B7-H1. IL-1β neutralization additionally reduced Treg induction by B7-H1-/- ATP-competitive mTOR inhibitor-exposed DC, suggesting that IL-1β and B7-H1 act additively to promote Treg induction by these DC. These findings establish a RAPA-resistant mTORC1 pathway that acts through SOCS3 and STAT3 to regulate DC B7-H1 expression and Treg induction.
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Li, Haiyan S., Cliff Y. Yang, Kalyan C. Nallaparaju, Huiyuan Zhang, Yong-Jun Liu, Ananda W. Goldrath, and Stephanie S. Watowich. "The signal transducers STAT5 and STAT3 control expression of Id2 and E2-2 during dendritic cell development." Blood 120, no. 22 (November 22, 2012): 4363–73. http://dx.doi.org/10.1182/blood-2012-07-441311.
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Abstract Cytokines and transcription factors play key roles in dendritic cell (DC) development, yet information about regulatory interactions between these signals remains limited. Here we show that the cytokines GM-CSF and Flt3L induce the transcriptional mediators Id2 and E2-2 and control DC lineage diversification by STAT–dependent pathways. We found that STAT5 is required for tissue CD103+ DC generation and plasmacytoid DC (pDC) suppression in steady state or response to GM-CSF. STAT5 stimulates GM-CSF–dependent expression of Id2, which controls CD103+ DC production and pDC inhibition. By contrast, pDCs, but not CD103+ DCs, are dependent on STAT3. Consistently, STAT3 stimulates Flt3L-responsive expression of the pDC regulator Tcf4 (E2-2). These data suggest that STATs contribute to DC development by controlling transcription factors involved in lineage differentiation.
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Rosborough, Brian, Ben Matta, Heth Turnquist, and Angus Thomson. "mTORC2 negatively regulates DC PD-L1 and IL-10 through SOCS3 and STAT3 (172.34)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 172.34. http://dx.doi.org/10.4049/jimmunol.188.supp.172.34.
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Abstract The mammalian Target of Rapamycin (mTOR) is a central regulator of dendritic cells (DC) that functions in two independent complexes, mTOR complex (mTORC) 1 and 2. Rapamycin (RAPA) is a selective inhibitor of mTORC1, whereas novel ATP-competitive mTORC1/2 inhibitors (Torin1) inhibit both complexes. The immunoregulatory function of RAPA-resistant mTORC2 in DC is unknown. C57BL/6, PD-L1-/-, IL-6-/-, IL-10-/-, IL-12/23p40-/-, Ebi3-/-, interferon regulatory factor (IRF)1-/-, or FoxO1/3/4-/- bone marrow cells were cultured in GM-CSF and IL-4 to generate CD11c+ DC. RAPA or Torin1 was added on d2, and LPS added on d7. DC phenotype and signaling was assessed (d8) by flow cytometry and immunoblot, respectively. While RAPA reduced PD-L1, mTORC1/2 inhibition selectively upregulated PD-L1 expression on DC in a STAT3-dependent manner in unstimulated and LPS-stimulated DC. Whereas RAPA reduced IL-10 secretion, mTORC1/2 inhibition augmented IL-10 secretion following LPS stimulation. The PD-L1 regulator, IRF1, and FoxO, a STAT3 regulator, were not required for PD-L1 upregulation. PD-L1 upregulation on mTORC1/2-inhibited DC did not require autocrine IL-6, IL-10, IL-12/23, or IL-27. SOCS3, a negative regulator of STAT3, was reduced dramatically in mTORC1/2-inhibited, but not RAPA-exposed DC. mTORC2 negatively regulates STAT3 in DC through SOCS3. Blockade of mTORC2 signaling enhances PD-L1 expression and IL-10 secretion. These novel findings establish mTORC2 as a key regulator of DC function.
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Singh, Pratibha, Jonathan Hoggatt, Peirong Hu, Jennifer M. Speth, Seiji Fukuda, Richard M. Breyer, and Louis M. Pelus. "Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells." Blood 119, no. 7 (February 16, 2012): 1671–82. http://dx.doi.org/10.1182/blood-2011-03-342428.
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Abstract Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E2 (PGE2) is required for optimal Flt3 ligand–mediated DC development and regulates expression of the Flt3 receptor on DC-committed progenitor cells. Inhibition of PGE2 biosynthesis reduces Flt3-mediated activation of STAT3 and expression of the antiapoptotic protein survivin, resulting in increased apoptosis of DC-committed progenitor cells. Reduced DC development caused by diminished PGE2 signaling is reversed by overexpression of Flt3 or survivin in DC progenitors and conversely is mimicked by STAT3 inhibition. PGE2 regulation of DC generation is specifically mediated through the EP1 and EP3 G protein PGE2 receptors. These studies define a novel DC progenitor regulatory pathway in which PGE2 signaling through EP1/EP3 receptors regulates Flt3 expression and downstream STAT3 activation and survivin expression, required for optimal DC progenitor survival and DC development in vivo.
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Peikert, Tobias, Kathleen Coughlin, Virginia Van Keulen, Michael Hansen, and Larry Pease. "Regulatory CD4+CD25+FOXP3+ T-cells can be Converted into Cytotoxic Effectors (40.36)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 40.36. http://dx.doi.org/10.4049/jimmunol.182.supp.40.36.
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Abstract Background: Binding of the human IgM antibody B7-DC XAb to B7-DC on dendritic cells (DC) has profound immune modulatory effects. It enhances antigen presentation by DC, repolarizes T-helper (Th) 2 to Th1 cell responses, rapidly generates cytotoxic effectors and reprograms regulatory T-cells (Treg) into non-suppressive, cytokine producing autoimmune effectors. We hypothesized that co-culture of B7-DC XAb treated DC (DCXAb) with Treg results in the rapid generation of cytotoxic effectors. Methods: Bone marrow derived DC from wild type C57BL6 mice (WT-B6) were treated for 24 hours with either B7-DC XAb or a control human IgM antibody in the presence of melanoma cell lysate (B16). Subsequently, DCXAb were co-cultured with Treg (CD4+CD25+FOXP3+), Non-Treg (CD4+, CD25-), cytotoxic CD8+ T-cells isolated from WT-B6 mice and Treg from CD8 knockout mice (CD8 -/-). After re-isolation these T-cells were used in cytotoxic T-lymphocyte (CTL) assays targeting B16 and Thymic lymphoma (EL4) tumor cells. Results: Treg isolated from either WT-B6 mice or CD8 -/- mice co-cultured with B16 lysate treated DCXAb but not control antibody treated DC transformed into cytotoxic effectors targeting B16 but not EL4 tumor cells. Their level of cytotoxicity was comparable to that of CD8+ cells co-cultured with DCXAb. In contrast Non-Treg co-cultured with DCXAb did not kill in similar CTL assays. Conclusion: Co-culture of Treg with antigen treated DCXAb rapidly generates antigen specific cytotoxic effectors.
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Levitt, Jonathan, Indu Ramachandran, and David Spencer. "The protein tyrosine phosphatase, SHP-1, is an intrinsic central regulator of dendritic cell function (113.8)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 113.8. http://dx.doi.org/10.4049/jimmunol.186.supp.113.8.
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Abstract Dendritic cells (DCs) initiate proinflammatory or regulatory T cell responses, depending on their activation state. Despite extensive knowledge of DC-activating signals, mechanisms of DC-inhibitory signals are less well understood. We show that the SH2-domain-containing protein tyrosine phosphatase, SHP-1, is an important inhibitor of DC signaling that targets multiple activation pathways. Downstream of TLR4, SHP-1 showed increased interactions with several proteins including IRAK-4, and modulated LPS signaling through the inhibition of NF-κB, AP-1, ERK and JNK activity, while enhancing p38 activity. In addition, SHP-1 inhibited pro-survival signaling modulated through AKT activation. Further, SHP-1 inhibited CCR7 protein levels and CCR7 mediated cytokine expression. Inhibition of SHP-1 in DCs enhanced proinflammatory cytokines, IL-6, IL-12 and IL-1β, promoted survival and increased the rate DC migration from the periphery to draining lymph nodes. In vivo administration of SHP-1-inhibited DCs loaded with antigen, significantly induced the expansion of antigen-specific cytotoxic T cells and inhibited Foxp3+ regulatory T cell proliferation compared to unmodified DCs. When used in a vaccination protocol, SHP-1-inhibited DCs significantly reduced progression of pre-established mouse melanoma and prostate tumors. Taken together, these data demonstrate that SHP-1 is an intrinsic global regulator of DC function, controlling many facets of T cell-mediated immune responses.
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Cravedi, Paolo, and Sistiana Aiello. "Regulatory T cells under scrutiny." Current Opinion in Organ Transplantation 9, no. 3 (September 2004): 301–6. http://dx.doi.org/10.1097/01.mot.0000129650.73005.dc.
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Mann, Elizabeth, Jie Shi, Dezhi Wang, Huihong Zhai, Shi Jin, Weiwei Jiang, and Xuhang Li. "Loss of regulatory intestinal dendritic cell subsets during gut inflammation in humans and mice (MUC2P.830)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 68.14. http://dx.doi.org/10.4049/jimmunol.192.supp.68.14.
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Abstract Background: Dendritic cells (DC) and macrophages (Mφ) mediate intestinal immune tolerance. Recent evidence suggests intestinal CD103+CD11b- DC are involved in generation of regulatory T cells (T-reg), with CD103+CD11b+ DC stimulating Th17 cell differentiation. Information regarding gut DC function during inflammation is scarce. Methods: We compared murine and human gut DC and Mφ in the steady state and during intestinal inflammation, by flow cytometry. Results: Proportions of CD103-CD64+ Mφ were enhanced in the inflamed IL-10 knockout (KO) murine colon compared to WT, alongside a loss of CD103+CD11b- DC. Proportions of CD4+FoxP3+ T-reg were reduced in the inflamed IL-10 KO colon, with enhanced production of IL-17A and TNFα by T cells but a loss of regulatory TGFβ production by CD103+ DC. Proportions of CD103-CD64+ Mφ were also enhanced in the human Crohn’s disease colon compared to non-inflamed control tissue (diverticulitis), alongside a loss of CD103+ DC. CD103 was co-expressed with either CD141 or CD1c on human intestinal DC, corresponding to CD103+CD11b- and CD103+CD11b+ murine DC respectively. Proportions of all CD103+ gut DC subsets were reduced in human Crohn’s disease. Conclusions: Lack of IL-10 may skew DC and Mφ differentiation in the gut, leading to loss of DC able to generate T-reg. Further experiments will determine the ability of intestinal DC and Mφ subsets to stimulate specific T cell responses in vitro and the roles of IL-10 and TGFβ during this process.
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Delluc, Stephanie, Auguste Gaston, Carmen Marchiol-Fournigault, Didier Fradelizi, Armelle Regnault, Kim Hanh Le Quan Sang, Lea Tourneur, Gilles Chiocchia, and Agnes Buzyn. "Depletion of Regulatory T Cells Dramatically Improves DC-Based Immunization Against Acute Myeloid Leukemia." Blood 108, no. 11 (November 16, 2006): 3694. http://dx.doi.org/10.1182/blood.v108.11.3694.3694.
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Abstract Dendritic cell (DC)-based vaccination is a promising approach to enhance anti-tumor immunity that could be considered for patients with high risk acute myeloid leukemia (AML). We have already shown in human that DC pulsed with eluted peptides (EP) from autologous AML blasts (DC/EP) are able to induce CD4+ and CD8+ anti-leukemic immune response in vitro (Delluc S, Haematologica, 2005). In order to optimize this vaccination strategy for AML patients we developed a pre-clinical murine model. C57/Bl6 mice were vaccinated by DC pulsed or not with peptides eluted from the syngenic C1498 myelomonocytic leukemic cell line in a prophylactic setting. Injection of DC/EP induced an anti-leukemic response as shown by the cytotoxic activity of CD4 T cells, whereas the injection of unpulsed DC induced a NK cell-mediated cytotoxicity against C1498 cells. In vivo depletion of CD4 T cells or NK cells abrogated the protective effect induced by DC/EP (p=0.02) or DC (p=0.06) vaccination, respectively, confirming their critical role in preventing leukemic outgrowth. However, late C1498 re-challenge showed that the anti-leukemic immune response was insufficient to protect DC/EP vaccinated mice from death, suggesting an ineffective or absent long-lived memory response. Since several populations of T cells have regulatory properties potentially inhibiting anti-tumor responses, we hypothesized that CD25+ cell-depletion in vivo could enhance the protection induced by vaccination. Indeed, we observed a dramatic improvement of the survival of mice treated by an anti-CD25 antibody before vaccination compared to mice vaccinated by DC/EP alone (p<0.01). More interestingly, CD25 depletion allowed the generation of long-lived immune responses since mice were protected from a late re-challenge by C1498 cells. Our results strongly suggest that depletion of regulatory CD25 T cells before DC-based vaccination should be considered for immunotherapy of weakly immunogenic tumors such as AML.
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Zhang, Shengbo, Hannah D. Coughlan, Mitra Ashayeripanah, Simona Seizova, Andrew J. Kueh, Daniel V. Brown, Wang Cao, et al. "Type 1 conventional dendritic cell fate and function are controlled by DC-SCRIPT." Science Immunology 6, no. 58 (April 2, 2021): eabf4432. http://dx.doi.org/10.1126/sciimmunol.abf4432.
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The functional diversification of dendritic cells (DCs) is a key step in establishing protective immune responses. Despite the importance of DC lineage diversity, its genetic basis is not fully understood. The transcription factor DC-SCRIPT is expressed in conventional DCs (cDCs) and their committed bone marrow progenitors but not in plasmacytoid DCs (pDCs). We show that mice lacking DC-SCRIPT displayed substantially impaired development of IRF8 (interferon regulatory factor 8)–dependent cDC1, whereas cDC2 numbers increased marginally. The residual DC-SCRIPT–deficient cDC1s had impaired capacity to capture and present cell-associated antigens and to secrete IL-12p40, two functional hallmarks of this population. Genome-wide mapping of DC-SCRIPT binding and gene expression analyses revealed a key role for DC-SCRIPT in maintaining cDC1 identity via the direct regulation of cDC1 signature genes, including Irf8. Our study reveals DC-SCRIPT to be a critical component of the gene regulatory program shaping the functional attributes of cDC1s.
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Fan, Ji, and Annette J. Schlueter. "Chronic ethanol ingestion induces peripheral tolerance by dendritic cells (36.21)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S16. http://dx.doi.org/10.4049/jimmunol.178.supp.36.21.
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Abstract As initiators of immune responses, dendritic cells (DCs) are required for antigen specific activation of na·ve T cells in the defense against infectious agents. The immune dysfunction in chronic alcoholics could be due to impaired immunostimulatory function or enhanced regulatory function of DCs by exposure to ethanol. Using a murine model of alcoholism, we previously assessed the ability of ethanol exposed DCs to stimulate T cell proliferation. (In this model, C57Bl/6 mice were administrated 20% ethanol in their drinking water, and maintained for 4 or 16 weeks without evidence of stress reactions.) DC chronically exposed to EtOH for 4 or 16 weeks were found to have decreased DC antigen presenting ability and induced hyporesponsiveness of allogenic T cells in mixed leukocyte reaction. In order to understand what mechanism was behind this phenomenon, we investigated whether regulatory T cells could be induced by DC from the same murine model of alcoholism. CFSE labeled splenocytes from OTII mice were transferred to syngeneic recipient mice on day 1. On day2 fresh splenic DC were purified on autoMACS, loaded with OVA peptide 329–337, and transferred to the same recipient mice. On day 4, the CD4+Foxp3+ T cell compartment in CFSE labeled (OTII) splenocytes was defined using flow cytometry. The results showed regulatory T cells were increased in response to contact with EtOH exposed DC. Meanwhile IL10 production by OTII CD4 T cells increased and IFN-gamma production decreased. We also found in EtOH exposed DC that PIR A/B expression (a regulatory DC marker) was increased, which might explain why EtOH exposed DC could induce peripheral tolerance as shown above. Additional phenotypic and functional characterization of these EtOH induced rDC subsets are in progress. Supported by NIH RO1 AA014405 and AA014406.
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Si, Chuanping, Ruihua Zhang, Yuan Hu, Hui Zhang, and Huabao Xiong. "Distinct roles of dendritic cell-derived iNOS in the control of effective and regulative dendritic cell differentiation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 59.2. http://dx.doi.org/10.4049/jimmunol.196.supp.59.2.
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Abstract The immune system exists in a delicate equilibrium between response and tolerance. Dendritic cells (DC) are a plastic lineage able to process and integrate signals from the microenvironment. But the regulation how DCs differentiate to effective or regulatory DC cells are incompletely understood. Inducible nitric oxide synthase (iNOS) derived NO plays critical roles in immune suppression of immune cells. But, it is still not clear what the function of DC cells-derived iNOS is in the regulation in inflammatory diseases. In this study, we demonstrated that DC-derived iNOS regulates balance of effective and regulatory DC cell differentiation. iNOS deficient mice displayed an increased effective DC phenotypes, whereas the percentage of regulatory DCs were comparable in wild-type and iNOS deficient mice in vivo and in vitro. The results were further supported by increased effective DCs from iNOS−/− BMDC cells. Activation of DCs by LPS/IFNg resulted in the expression of iNOS in WT mice. The iNOS inhibitor L-NIL enhanced effective DCs differentiation, mimicking the effect observed in iNOS deficient mice. NO donor SNAP suppressed effective DCs. iNOS−/− DCs result in more enhanced T cell activation. iNOS−/− mice infected with Citrobacter Rodentium led to more severe intestinal inflammation compared to WT mice and the results were correlated with more inflammatory cells infiltration in iNOS−/− in colon tissues. And iNOS−/− mice showed increased effective DCs in colon tissues than that in WT mice. Our results suggest that DC-derived iNOS negatively controls effective DC development and targeting DC-derived iNOS would lead to the new therapies for autoimmune/inflammatory diseases.
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Broggi, Achille, Caterina Vitali, Francesca Mingozzi, Giorgio Raimondi, Ivan Zanoni, and Francesca Granucci. "Regulatory T cell conversion by migratory but not lymphoid tissue resident dendritic cells (50.11)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 50.11. http://dx.doi.org/10.4049/jimmunol.186.supp.50.11.
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Abstract There is evidence that dendritic cells (DCs) induce peripheral tolerance. Although studies on specific DC subsets have proven their ability to induce regulatory T cell conversion (iTreg cells), little is know about the DC subtypes actually able to promote peripheral CD4+ T cell tolerance to autoantigens in vivo. Here, we show that, when autoantigen presentation is not confined to specific DC subsets but is extended to all conventional DCs, steady state migratory DCs (ssmDCs) possess unique ability to induce antigen-specific iTreg cells in cutaneous lymph nodes (CLNs). Diversely, lymphoid tissue resident DCs do not show this capacity. Moreover, DC-derived CCL22 contributes to the retention of iTreg cells in CLNs and skin. Therefore migratory DCs represent the DC population devoted to the maintenance of peripheral self-tolerance.
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Benencia, Fabian, and George Coukos. "T regulatory cell depletion can boost DC-based vaccines." Cancer Biology & Therapy 4, no. 6 (June 2005): 628–30. http://dx.doi.org/10.4161/cbt.4.6.1766.
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Bianchi, Joana, Rita I. Azevedo, Ana I. S. Vieira, Dário Ligeiro, Cláudia L. da Silva, and João F. de Lacerda. "Phenotypic and functional characterisation of expanded antigen-specific regulatory T cells (Ag-sp Treg), towards clinical translation." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 57.2. http://dx.doi.org/10.4049/jimmunol.202.supp.57.2.
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Abstract Treg infusion for graft-versus-host-disease treatment has been increasingly investigated. Yet, Treg of unknown specificity may suppress graft-versus-leukemia. To ascertain the factors affecting Ag-sp Treg potency and specificity of suppression, we assessed Ag-sp Treg phenotype and function within different expansion conditions and suppression assay (SA) milieus. Ex vivo Treg were co-cultured with monocyte-derived dendritic cells (DC) presenting allogeneic Ag directly (allo-DC) or indirectly (self-DC loaded with allo-lysate). Suppression of effector proliferation and cytokine secretion was assessed in SA with the same DC as in expansion (original) or 3rd party DC (3P) from various donors. Ag-sp Treg significantly suppressed Tcon and CD8+ T cell responses to original DC. Directly expanded cells suppressed responses to Ag presented direct and indirectly; however, indirectly expanded cells were less suppressive of responses to allo-DC. More potent Treg were less specific in their suppression of Tcon. Still, responses to 3P donors with MHC matches to original DC donor were significantly more suppressed than responses to unmatched 3P donors. Potency of suppression was also negatively correlated to expression of CD86 and CD83 in DC. Finally, FlowSOM analysis showed minimal overlap between Ag-sp Treg and activated Tcon phenotypes, suggesting Ag-sp Treg were pure. K-means clustering of Ag-sp Treg expression of CD137, CD154, CTLA-4, PD-1, CTLA-4 and HLA-DR identified clusters that may be correlated to Treg function. We propose the specificity of Ag-sp Treg function in the inflammatory milieu is a result of Treg phenotype, type of responders, DC co-stimulation and degree of MHC match between expansion DC and DC present in the milieu.
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Hoyer, Katrina, Sara Isakson, Shoshana Katzman, and Abul Abbas. "Dendritic cells initiate early autoimmunity in the absence of functional regulatory T cells (115.7)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 115.7. http://dx.doi.org/10.4049/jimmunol.186.supp.115.7.
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Abstract BALB/c IL-2-KO mice develop systemic autoimmunity, dying within 4 wks from autoimmune hemolytic anemia. Disease in these mice is Th1-mediated, and IFNγ production is required for early autoimmunity. We asked whether APC are required for IFNγ production by T cells in the IL-2-KO mouse. Our data show that APC:T cell interactions through B7, but not via B cells, are necessary for IFNγ production in the absence of IL-2, suggesting that dendritic cells (DC) mediate this alteration. Disease is marked by DC accumulation, activation and elevated cytokine production, including IL-12 and type1-interferons. The depletion of either conventional (cDC) or plasmacytoid (pDC) significantly augmented the survival of IL-2-KO mice, demonstrating that DC contribute to the progression of autoimmunity. In the absence of IL-12, T cell activation and disease is only moderately altered, thus Th1 differentiation and IFNγ induction as a part of the underlying kinetics of autoimmunity is primarily IL-12-independent. Elimination of type 1 interferon signals in addition to IL-12 further augmented survival, indicating that cytokines derived from both pDC and cDC contribute to disease severity. Enhanced DC function is not dependent on T cell activation as DC in an environment without overt T cell activation are still functionally activated. Overall, our data suggest that DC activation can be an initiating event during the development of disease and thus DC are critical regulators of autoimmune development.
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Nicholson, Lindsay, Emily Mavin, Lynne Minto, Julie Irving, Anne Dickinson, and Xiao-Nong Wang. "Gene Expression Profiling Implicates Attenuation of NFkB Signalling By Regulatory T Cells in Modulating Dendritic Cell Function." Blood 126, no. 23 (December 3, 2015): 3068. http://dx.doi.org/10.1182/blood.v126.23.3068.3068.
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Abstract Dendritic cells (DC) play a key role in the pathogenesis of Graft versus Host Disease (GvHD), a complication of haematopoietic stem cell transplantation and offer an attractive target for therapy. Regulatory T cells (Treg) have a potent immunoregulatory effect on the maturation and the antigen-presenting cell (APC) function of DC and adoptive transfer of Treg is highly efficacious in the induction of tolerance in an experimental model of GvHD and has entered Phase I clinical trials. Several mechanisms of suppression have been proposed, including Treg acting directly on DCs, attenuating their antigen-presenting and co-stimulatory functions by arresting their maturation. However, the molecular basis underpinning these effects in DCs remains ill-defined. We investigated the effect of Treg treatment on DCs by conducting gene expression profiling and confirmed the functional consequences using downstream assays. Immature, mature and Treg-treated DCs were generated from immuno-magnetic isolated monocytes (im-DC, mat-DC and Treg-DC, respectively) and moDC populations were generated using a well-established 6 day culture with GM-CSF and IL-4, followed by 24 hour LPS maturation. Treg were added on day 3 of culture at a 3:1 ratio. All cell populations were harvested on day 7 and sorted via FSC/SSC/CD3neg gating to remove Treg present in the co-culture and control for any changes in gene expression caused by shear stress. Gene expression profiling was carried out using the Illumina HumanHT12 microarray platform. Data was processed using R/Bioconductor workflows and the functional significance of differentially expressed genes was evaluated using Ingenuity Pathway Analysis software. Mat-DC and Treg-DC expression profiles were compared relative to the im-DC for data analysis. Upon LPS treatment, the levels of 1834 unique genes were differentially regulated in mat-DC by at least twofold (862 genes upregulated/972 downregulated) compared to the im-DC counterparts. In the Treg-DC, 1326 unique genes were differentially modulated (633 genes upregulated/693 genes downregulated). Microarray analysis of the CD markers identified a higher expression of the previously identified surface markers CD80, CD83 and CD86 in the mat-DC compared to the Treg-treated counterpart (validated by flow cytometry), confirming the semi-mature phenotype. Novel findings from the dataset include the reduction of the endocytotic-related genes, CD206 and CD209, in the Treg-DCs compared to the im-DC and this reduction manifested functionally in an impaired antigen uptake, as assessed by FITC-Dextran. Additionally, the surface marker, CD38, was downregulated in the Treg-DC compared to the mat-DC, confirmed by flow cytometry. CD38 has been shown to be NFκB-dependent and a marker of maturation in monocyte-derived DCs, further supporting the semi-mature phenotype. Furthermore, CD38 is functionally involved in CD83 expression and IL-12 induction. We assessed IL-12 cytokine secretion by Treg-treated DCs and showed a significantly reduced level of induction compared to mat-DC (p=0.0079). Pathway analysis revealed NFκB-related genes to be downregulated in the Treg-DC compared to the mat-DC. These differentially expressed genes included the TLR-adaptor protein, MYD88, the NFκB subunit, RELB and an inhibitor of NFκB, NFκB1A. This finding, coupled to the importance of NFκB signalling pathway in DC function, prompted us to investigate it at the functional level by measuring levels of phosphorylation of serine 536 of the RelA subunit as a marker of activity in response to LPS stimulation. DC cultured in the absence of Tregs (mat-DC) showed significantly higher levels of Ser536 phosphorylation when compared to those unstimulated cells (im-DC) (p= 0.0018). Concordant with the gene expression data, Treg-treated DCs (Treg-DC), showed a significantly attenuated NFκB activation when compared to their LPS-stimulated DCs counterparts (p = 0.0191), however, signalling was not completely abolished compared to those unstimulated DCs (p= 0.0003). In conclusion, gene expression profiles of Treg-treated DCs are significantly different to their mat-DC and im-DC counterparts. Here, we present the novel finding that Tregs modulate DC function, in part, by attenuation of the NFkB signalling pathway, arresting the DCs at a semi-mature phenotype, as evidenced by expression arrays and functional assays. Disclosures No relevant conflicts of interest to declare.
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Kronenberger, Konrad, Robert S. Liwski, Tara Trenholm, and Kenneth A. West. "Prolonged FRC-DC interaction negatively affects DC-T cell crosstalk (88.10)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S140. http://dx.doi.org/10.4049/jimmunol.178.supp.88.10.
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Abstract While Fibroblastic Reticulum Cells (FRC) of the lymph node (LN) are known to produce chemokines responsible for the migration of naïve T cells and DC, little is known about their interactions with these cells and their influence on DC and T cell activation. Therefore, we have evaluated the interaction between DC, FRC and T cells in an in vitro model. For the generation of FRC cells lymph nodes of BALB/c mice were isolated and cultured ex vivo. After co culture with FRC DCs were characterized by FACS analysis concerning their survival rate, maturation state and expression of cell surface molecules as well as for their production of soluble cytokines. The ability of DC to induce T cell proliferation was evaluated using the D011.10 TCR transgenic system and CFSE labeling. Our in vitro culture method leads to a highly homogeneous FRC population regarding expression of gp38, ER-TR 7, CD44 and V-CAM. Confocal microscopy analysis demonstrated that DC migrated to FRC where they made physical contact leading to stable associations in vitro as well as in vivo in the LN after DC were injected s.c.. Co incubation of DC with FRCs resulted in a complete down regulation of CD40 and partial decrease of co stimulatory molecules. Furthermore there was a strongly diminished ability of these DC to induce a peptide specific proliferation of naïve T cells although a clear CD25 up regulation could be detected. It remains to be investigated whether these CD25 positive T cells show a regulatory phenotype. Our results demonstrate that LN-FRC provide a milieu that may induce tolerogenic DCs which then drive naïve T cells to a rather regulatory phenotype.
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Housley, William J., Catherine A. O'Conor, and Robert B. Clark. "PPARgamma drives conversion of inducible Tregs by stimulating dendritic cell production of retinoic acid (89.23)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 89.23. http://dx.doi.org/10.4049/jimmunol.182.supp.89.23.
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Abstract Regulatory T cells are critical in preventing autoimmunity, and peripherally-generated inducible regulatory T cells (iTregs) may also play an important regulatory role. Retinoic acid (RA) has been shown to enhance iTreg generation, and specific subsets of gastrointestinal (GI) dendritic cells (DCs) enhance iTreg generation through production of RA. The factors that regulate DC secretion of RA are unknown. We postulated that the nuclear hormone receptor PPARγ may regulate murine DC production of RA and DC-mediated generation of iTregs. PPARγ ligands are expressed in the GI tract and both down-regulate immune responses and ameliorate murine models of autoimmunity. Using splenic DCs and the synthetic PPARγ ligand Ciglitizone (Cig), we show that PPARγ activation in vitro increases iTreg generation. This increase can be blocked by LE 540, an RA inhibitor, or Citral, an RA synthesis inhibitor, and is associated with an upregulation of mRNA for RA-synthesis enzymes. In vivo administration of Cig also increases splenic DC expression of RA-synthesis genes, and, ex-vivo, these DCs enhance iTreg generation. Finally, the PPARγ-inhibitor GW9662 blocks both the baseline iTreg generation and the Cig-induced increase in iTreg generation. Our results show that PPARγ activation can increase DC RA production and DC-mediated iTreg generation, suggesting a new role for PPARγ in immunoregulation (NIH: 1R56AI072533-01A1).
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Escors, David, Luciene Lopes, Rongtuan Lin, John Hiscott, Shizuo Akira, Roger J. Davis, and Mary K. Collins. "Targeting dendritic cell signaling to regulate the response to immunization." Blood 111, no. 6 (March 15, 2008): 3050–61. http://dx.doi.org/10.1182/blood-2007-11-122408.
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Abstract Dendritic cells (DCs) are key regulators of the immune system; they capture antigens and then can either stimulate an immune response or induce tolerance. Our aim was to activate individual DC signaling pathways to regulate the immune response. We therefore expressed constitutive activators of mitogen-activated protein kinase (MAPK) pathways or the interferon pathway, together with tumor antigens, using lentivectors. Triggering of p38 activated DCs substantially enhanced the antitumor immune response and prolonged survival of tumor-bearing mice. Activation of extracellular signal–regulated kinase (ERK) increased TGF-β expression while expression of a constitutively activated interferon regulatory factor-3 (IRF3) stimulated IL-10 secretion by DCs. ERK and IRF3 suppressed the immune response and stimulated expansion of regulatory T cells. These results provide a toolkit to regulate immune responses to viral vector or DC immunization; vaccine responses to foreign or tumor antigens can be enhanced and harmful responses to self-antigens or introduced transgenes can be reduced.
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Chung, Jin-Sung, Kota Sato, Irene I. Dougherty, Ponciano D. Cruz, and Kiyoshi Ariizumi. "DC-HIL is a negative regulator of T lymphocyte activation." Blood 109, no. 10 (February 6, 2007): 4320–27. http://dx.doi.org/10.1182/blood-2006-11-053769.
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Abstract T-cell activation is the net product of competing positive and negative signals transduced by regulatory molecules on antigen-presenting cells (APCs) binding to corresponding ligands on T cells. Having previously identified DC-HIL as a receptor expressed by APCs that contains an extracellular immunoglobulin (Ig)–like domain, we postulated that it plays a role in T-cell activation. To probe this function, we created soluble recombinant DC-HIL, which we observed to bind activated (but not resting) T cells, indicating that expression of the putative ligand on T cells is induced by activation. Binding of DC-HIL to naive T cells attenuated these cells' primary response to anti-CD3 antibody, curtailing IL-2 production, and preventing entry into the cell cycle. DC-HIL also inhibited reactivation of T cells previously activated by APCs (secondary response). By contrast, addition of soluble DC-HIL to either allogeneic or ovalbumin-specific lymphocyte reactions augmented T-cell proliferation, and its injection into mice during the elicitation (but not sensitization) phase of contact hypersensitivity exacerbated ear-swelling responses. Mutant analyses showed the inhibitory function of DC-HIL to reside in its extracellular Ig-like domain. We conclude that endogenous DC-HIL is a negative regulator of T lymphocyte activation, and that this native inhibitory function can be blocked by exogenous DC-HIL, leading to enhanced immune responses.
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Salomon, B., P. Lorès, C. Pioche, P. Racz, J. Jami, and D. Klatzmann. "Conditional ablation of dendritic cells in transgenic mice." Journal of Immunology 152, no. 2 (January 15, 1994): 537–48. http://dx.doi.org/10.4049/jimmunol.152.2.537.
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Abstract Dendritic cells (DC) are professional Ag-presenting cells that play a major role in T cell-mediated immune responses and in thymocyte differentiation. To better analyze their physiological importance, we sought to generate transgenic mice presenting a conditional DC deficiency. We used a strategy based on the cell-specific expression of a suicide gene. The DC-targeted expression is obtained using HIV regulatory sequences; indirect evidence has suggested that these sequences control a preferential expression in DC. The suicide gene is the herpes simplex virus type 1 thymidine kinase (HSV1-TK) which allows conditional ablation of dividing HSV1-TK-expressing cells by converting nucleoside analogs such as ganciclovir (GCV) into toxic molecules. We generated transgenic mice expressing an HSV1-TK gene transcribed from HIV regulatory sequences. A low but significant HSV1-TK expression was observed in mature DC and DC precursors grown from granulocyte-macrophage colony-stimulating factor-supplemented bone marrow cultures. These HSV1-TK-expressing DC precursors are specifically killed by GCV. We next treated transgenic mice with GCV, and obtained a specific ablation of DC in spleen and thymus. Ninety percent of spleen DC could be depleted within a week, indicating a turnover rate of approximately 15% per day. Interestingly, this DC depletion always correlated with a major thymic atrophy and disappearance of CD4+CD8+ thymocytes. This animal model should help to assess the physiological role of DC in the immune response and in thymocyte differentiation. It should also help to appreciate the consequences of DC dysfunction in pathological situations, such as HIV-infection or allograft rejection.
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Maksimow, Mikael, Mari Miiluniemi, Fumiko Marttila-Ichihara, Sirpa Jalkanen, and Arno Hänninen. "Antigen targeting to endosomal pathway in dendritic cell vaccination activates regulatory T cells and attenuates tumor immunity." Blood 108, no. 4 (August 15, 2006): 1298–305. http://dx.doi.org/10.1182/blood-2005-11-008615.
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Abstract Lymphoma cells are malignant cells of the T- or B-cell lineage that often express many surface markers inappropriately, yet are not recognized as abnormal by the immune system. We modeled this situation by inoculating ovalbumin-expressing E.G7-OVA lymphoma cells into mice that expressed ovalbumin as a self antigen in pancreatic islets, and investigated the efficacy of dendritic cell (DC) vaccination in these mice. Although vaccination with DC-expressing ovalbumin induced strong cytotoxic T-cell immunity, which led to clearance of E.G7-OVA lymphoma cells in naive C57BL/6 mice, DC vaccination was ineffective in mice expressing ovalbumin as a self antigen. Antigen modification to increase its processing via the endosomal processing pathway dramatically increased CD4 T-cell activation but paradoxically, impaired the protective effect of DC vaccination even in naive mice. Depletion of CD25+ T cells (regulatory T cells [Tregs]) prior to vaccination restored the efficacy of DC vaccination and allowed eradication of lymphoma also in mice expressing ovalbumin as a self antigen. We conclude that lymphoma cells may be eradicated using DC vaccination if activation of CD25+ Tregs is simultaneously inhibited, and that intentionally enhanced endosomal antigen processing in DC vaccines may shift the balance from CD4 T-cell help toward stimulation of Tregs.
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Humphreys, Tricia L., Lang Li, Xiaoman Li, Diane M. Janowicz, Kate R. Fortney, Qianqian Zhao, Wei Li, et al. "Dysregulated Immune Profiles for Skin and Dendritic Cells Are Associated with Increased Host Susceptibility to Haemophilus ducreyi Infection in Human Volunteers." Infection and Immunity 75, no. 12 (September 24, 2007): 5686–97. http://dx.doi.org/10.1128/iai.00777-07.
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ABSTRACTIn experimentally infected human volunteers, the cutaneous immune response toHaemophilus ducreyiis orchestrated by serum, polymorphonuclear leukocytes, macrophages, T cells, and myeloid dendritic cells (DC). This response either leads to spontaneous resolution of infection or progresses to pustule formation, which is associated with the failure of phagocytes to ingest the organism and the presence of Th1 and regulatory T cells. In volunteers who are challenged twice, some subjects form at least one pustule twice (PP group), while others have all inoculated sites resolve twice (RR group). Here, we infected PP and RR subjects withH. ducreyiand used microarrays to profile gene expression in infected and wounded skin. The PP and RR groups shared a core response toH. ducreyi. Additional transcripts that signified effective immune function were differentially expressed in RR infected sites, while those that signified a hyperinflammatory, dysregulated response were differentially expressed in PP infected sites. To examine whether DC drove these responses, we profiled gene expression inH. ducreyi-infected and uninfected monocyte-derived DC. Both groups had a common response that was typical of a type 1 DC (DC1) response. RR DC exclusively expressed many additional transcripts indicative of DC1. PP DC exclusively expressed differentially regulated transcripts characteristic of DC1 and regulatory DC. The data suggest that DC from the PP and RR groups respond differentially toH. ducreyi.PP DC may promote a dysregulated T-cell response that contributes to phagocytic failure, while RR DC may promote a Th1 response that facilitates bacterial clearance.
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Ogasawara, Masahiro, Shinsuke Asanuma, Shinsuke Noguchi, Atsushi Yasumoto, Akinori Wada, Shuuichi Ohta, Masanobu Nakata, et al. "Large Scale Expansion of Human Dendritic Cells with Regulatory Function from Peripheral Blood Monocytes Employing Leukapheresis and Rapamycin for Clinical Trials." Blood 110, no. 11 (November 16, 2007): 1204. http://dx.doi.org/10.1182/blood.v110.11.1204.1204.
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Abstract Regulatory T cells (Treg) exert pivotal roles on the induction and maintenance of peripheral tolerance. Adoptive transfer of Treg is a promising strategy to control acute GVHD. However, in vitro expansion of Treg is costly, laborious and time-consuming (more than 3 weeks). As an alternative source, dendritic cells (DC) with regulatory function (DCreg) seem to be attractive, since DC are potent antigen presenting cells capable of regulating the initiation of various immune responses and can be generated in a relatively short term culture from peripheral blood (PB) monocytes. In the present study, we examined the feasibility of generating DCreg on a large scale from PB monocytes obtained by leukapheresis. PB mononuclear cells (range 1.8×109 to 3.1×109) were obtained from 5 healthy volunteers with informed consent by leukapheresis for 1–2 hours using a COBE Spectra apparatus. Immature DC were generated from isolated CD14+ monocytes by culturing with GM-CSF and IL4 with or without various concentrations of rapamycin for 5–7days. For maturation, immature DC were cultured with the addition of TNFα for 2 days. The yield of immature DC cultured with rapamycin (10ng/ml) was 8.4±3.6×107, constituting 4.2±1.8% of the initial PB mononuclear cells. FACS analysis showed that DC cultured with rapamycin (DC-rapa) had immature DC phenotype with CD14−, CD1a+, CD83−. But the surface expression of CD86, CD40, HLA-DR was much lower compared with control DC (DC-ctr) cultured without rapamycin. The reduction of the expression of CD86, CD40, HLA-DR was dependent of rapamycin dose and resistant to maturational stimulation of TNFα. DC-rapa showed very weak allostimulatory activity in a mixed lymphocyte culture (MLC) compared with DC-ctr, corresponding to the reduced expression of HLA-DR and costimulatory molecules. To further determine the types of cells involved, CSFE-labelled non-isolated CD4+ T cells were cultured with DC-rapa or DC-ctr for 7 days and the proliferating cells were identified by FACS analysis. DC-rapa inhibited the proliferation of CD4+CD25− alloreactive T cells by approximately 60% while the inhibitory effect of DC-rapa on CD4+ CD25+ cells was minimal. Neither the irradiation of DC nor the addition of IL2 altered the inhibition. Stimulation with both anti-CD3 and ani-CD28 moonoclonal antibodies coated on microbeads reversed the inhibition completely, suggesting the importance of the signals via T cell receptors and costimulatory molecules in the inhibition by DC-rapa. Double staining with anti-CD25 and anti-Foxp3 monoclonal antibodies revealed that DC-rapa increased the percentage and number of CD25+Foxp3+ Treg by approximately 2.6 times compared with DC-ctr during 7-day culture. In conclusion, these results demonstrated that immature DC induced with rapamycin have a potent immunoregulatory function including preferential expansion of Treg. To the best of our knowledge, this is the first demonstration that immunoregulatory DC can be generated on a large scale in relatively short term culture with rapamycin following leukapheresis. These findings have an important clinical implication to facilitate DC-based immunotherapy for acute GVHD.
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Bray, Sarah M., Lazar Vujanovic, and Lisa H. Butterfield. "Dendritic Cell-Based Vaccines Positively Impact Natural Killer and Regulatory T Cells in Hepatocellular Carcinoma Patients." Clinical and Developmental Immunology 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/249281.
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Immunotherapy of cancer must promote antitumor effector cells for tumor eradication as well as counteract immunoregulatory mechanisms which inhibit effectors. Immunologic therapies of cancer are showing promise, including dendritic cell-(DC-) based strategies. DC are highly malleable antigen-presenting cells which can promote potent antitumor immunity as well as tolerance, depending on the environmental signals received. Previously, we tested a peptide-pulsed DC vaccine to promote Alpha-fetoprotein (AFP-) specific anti-tumor immunity in patients with hepatocellular carcinoma (HCC), and reported on the CD8+T cell responses induced by this vaccine and the clinical trial results. Here, we show that the peptide-loaded DC enhanced NK cell activation and decreased regulatory T cells (Treg) frequencies in vaccinated HCC patients. We also extend these data by testing several forms of DC vaccinesin vitroto determine the impact of antigen loading and maturation signals on both NK cells and Treg from healthy donors and HCC patients.
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Berneman, Zwi N., Nathalie Cools, Viggo F. I. Van Tendeloo, Marc Lenjou, Griet Nijs, Dirk R. Van Bockstaele, and Peter Ponsaerts. "Dendritic Cell-Induced T Cell Non-Responsiveness Is Mediated by FOXP3+ and TGF-beta+IL-10+ CD4+ T Cells." Blood 108, no. 11 (November 16, 2006): 3891. http://dx.doi.org/10.1182/blood.v108.11.3891.3891.
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Abstract Dendritic cells (DC), the professional antigen presenting cells of the immune system, exert important functions both in induction of T cell immunity as well as of tolerance. Previously, it was accepted that the main function of immature DC (iDC) in their in vivo steady state condition is to maintain peripheral tolerance to self-antigens and that these iDC mature upon encounter of so-called danger signals and subsequently promote T cell immunity. However, a growing body of experimental evidence now indicates that traditional DC maturation can no longer be used to distinguish between tolerogenic and immunogenic properties of DC. In this study, we compared the in vitro stimulatory capacity of immature DC (iDC), cytokine cocktail-matured DC (CC-mDC) and poly I:C-matured DC (pIC-mDC) in the absence and presence of antigen. All investigated DC types could induce at least 2 subsets of regulatory T cells. We observed a significant increase in both the number of functionally suppressive transforming growth factor (TGF)-beta+ interleukin (IL)-10+ T cells as well as of CD4+CD25+FOXP3+ T cells within DC/T cell co-cultures as compared to T cell cultures without DC. The induction of these regulatory T cells correlates with in vitro T cell non-responsiveness after co-culture with iDC and CC-mDC, while stimulation with pIC-mDC resulted in reproducible cytomegalovirus pp65 or influenza M1 matrix peptide-specific T cell activation as compared to control cultures in the absence of DC. In addition, the T cell non-responsiveness after stimulation with iDC was shown to be mediated by TGF-beta and IL-10. Moreover, the suppressive capacity of CD4+ T cells activated by iDC and CC-mDC was shown to be transferable when these CD4+ T cells were added to an established T cell response. In contrast, addition of CD4+ T cells stimulated by pIC-mDC made responder T cells refractory to their suppressive activity. In conclusion, we hypothesize that DC have a complementary role in inducing both regulatory T cells and effector T cells, where the final result of antigen-specific T cell activation will depend on the activation state of the DC. This emphasizes the need for proper DC activation when T cell immunity is the desired effect, especially when used in clinical trials.
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Kurokawa, Masatsugu, Satoshi Konno, Ayumu Takahashi, Beverly Plunkett, Susan R. Rittling, Yutaka Matsui, Shigeyuki Kon, et al. "Regulatory role of DC-derived osteopontin in systemic allergen sensitization." European Journal of Immunology 39, no. 12 (October 14, 2009): 3323–30. http://dx.doi.org/10.1002/eji.200838970.
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Raimondi, Giorgio, and Angus W. Thomson. "Differential modulation of regulatory T cell function by pro-inflammatory cytokines (96.13)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 96.13. http://dx.doi.org/10.4049/jimmunol.182.supp.96.13.
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Abstract Little is known regarding the modulation of regulatory T cell (Treg) activity. Maturing dendritic cells (DC) secrete a cocktail of cytokines (R-cocktail) that liberates T cells from Treg suppression. IL-6 is one component, but others remain unknown. We performed microarray analysis of maturing DC and identified IL-12p40, TNFα, and Ebi3 as candidates. We developed a DC-free in-vitro suppression assay to test their function. As expected, addition of supernatant from maturing DC allowed T cells to resist suppression. Use of IL-6 increased T cell resistance significantly. Its combination with IL-12 or TNFα increased T cell resistance further. IL-12 and TNFα were interchangeable, suggesting redundant activity. The R-cocktail exerted its effect on T cells since a short pre-exposure before co-culture released them from suppression. On the other hand, Treg pre-exposure increased their suppressive capacity, indicating that the effect exerted on T cells was dominant. Unexpectedly, when we tested Ebi3, in the form of IL-27, we observed sustained Treg suppressive activity, an effect that was exerted specifically on Treg, as indicated by the pre-exposure experiment. This observation helps clarify the reported anti-inflammatory capacity of IL-27. Thus, pro-inflammatory cytokines exert distinct effects on T cells and Treg, promoting counter-balancing activities used by the immune system to finely tune its reactivity.
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Yan, Zhonghua, Sanjay Garg, Jonathan Kipnis, and Ruma Banerjee. "Modulation of extracellular redox remodeling by regulatory T cells (33.11)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 33.11. http://dx.doi.org/10.4049/jimmunol.182.supp.33.11.
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Abstract T cell activation and proliferation requires a reducing microenvironment that is provided by dendritic cells (DC). Naturally occurring CD4+CD25+ regulatory T cells (Treg) can suppress autoimmunity by inhibiting CD4+CD25- effector T cells (Teff). The mechanism is not fully understood. In this study, we have tested the hypothesis that inhibition by Treg cells of DC-induced extracellular redox remodeling is a component of the Treg immunosuppressive mechanism. We demonstrate that the increase in extracellular Cys concentration upon co-culture of DCs with Teff cells results from the system xc--dependent import of cystine, its conversion to glutathione, which is subsequently exported and degraded by γ-glutamyltranspeptidase and a dipeptidase, to furnish Cys. Suppression of DC-dependent Teff cell proliferation by Treg cells is correlated with a significant diminution in extracellular Cys concentration and is abrogated by addition of exogenous Cys. The decrease in the extracellular redox potential during T cell activation is associated with an increase in the levels of exofacial surface thiols in both DCs and T cells, which is diminished in the presence of Treg cells. This study elucidates the pathway of thiol release by DCs in response to T cell stimulation, demonstrates that Treg cells interfere with the process of extracellular redox remodeling and identifies a novel mechanism for immunomodulation.
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Fallarino, Francesca, Maria Letizia Barreca, Giorgia Manni, Giulia Scalisi, Emiliano Biasini, Marco Gargaro, and Giuseppe Manfroni. "Small molecule modulators of prion protein (PrpC) in Dendritic cells regulate inflammatory responses in a model of Multiple Sclerosis." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 121.2. http://dx.doi.org/10.4049/jimmunol.200.supp.121.2.
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Abstract Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for human multiple sclerosis, an autoimmune disease driven by differentiated Th1 and Th17 cells, and inflammatory dendritic cells (DCs). Recent data show that EAE is worsened in mice lacking PrPC protein and disease exacerbation has been attributed to T cells, which would differentiate into more aggressive effectors, when deprived of PrPC. Novel compounds, modulating PrPC activity, have been recently developed, although not tested in EAE models yet. Interestingly, by specific gene array studies, we found that PrPC was highly expressed in DCs and differentially expressed among selected DC subsets. Moreover, by using a series of computational, and biochemical assays we identified novel small molecules, able to modulate PrPC function in specific cell lines overexpressing PrPC. By employing such tools, we studied the impact of PrPC modulation in promoting regulatory DC subsets. To this aim, DCs were treated either with novel PrPC modulators or a reference PrPC binding molecule Fe (III)-TMPyP. Then, they were co-cultured with sorted naïve CD4+ T cells in vitro. Notably, we found a significant expansion of FOXP3+CD4+ T regulatory (Treg) cells in cultures containing DC subsets, which were pre-treated with the specific PrPC modulators. Moreover, in a EAE model, we showed that systemic administration of such PrPC regulators, resulted in significant reduction of disease severity, compared to untreated controls. Overall, our results suggest that PrPC modulation in selected DC subsets may represent a novel means to restrain inflammatory T cell effectors, resulting in reduced inflammation, demyelination, and axonal injury in a model of EAE.
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Seyerl, Maria, Stefanie Kirchberger, Otto Majdic, Joachim Seipelt, Christoph Jindra, Catharina Schrauf, and Johannes Stöckl. "B7-H1 (CD274) and sialoadhesin (CD169) on human dendritic cells induce IL-35 producing regulatory T cells (152.27)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 152.27. http://dx.doi.org/10.4049/jimmunol.186.supp.152.27.
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Abstract IL-35 is a heterodimer of EBV-induced gene 3 and of the p35 subunit of IL-12, and was identified as an inhibitory cytokine produced by natural regulatory T cells in mice, but not in humans. Here we demonstrate that DC activated by human rhinoviruses (R-DC) induce IL-35 production and release, as well as a suppressor function in CD4+ and CD8+ T cells derived from human peripheral blood but not in naïve T cells from cord blood. The induction of IL-35-producing T cells by R-DC was FOXP3-independent. We observed that, when we blocked B7-H1 and sialoadhesin on the R-DC side with specific mAb against both receptors, the induction of IL-35 was prevented. Thus, the combinatorial signal delivered by R-DC to T cells via B7-H1 and sialoadhesin is crucial for the induction of human IL-35 producing regulatory T cells. These results demonstrate a novel pathway and its components for the induction of immune-inhibitory T cells.
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Wang, Xinxin, Yaming Wang, Xiaolu Xu, Melissa Swiecki, Marco Colonna, and Yina Huang. "InsP4 negatively regulates dendritic cell cytokine secretion and migration to peripheral draining lymph nodes. (CAM1P.234)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 47.10. http://dx.doi.org/10.4049/jimmunol.192.supp.47.10.
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Abstract Inositol 1,3,4,5-tetrakisphosphate (InsP4) is a novel second messenger that is critical for T and B cell development and activation. However, whether InsP4 has a similar regulatory role in dendritic cell (DC) function is not yet known. We show here that InsP4 differentially regulates ERK and Akt signaling in response to LPS activation of bone marrow derived DCs (BMDCs). InsP4 supports ERK activation but negatively regulates Akt and its down-stream signals. Interestingly, endogenous migratory DCs from InsP4 deficient mice and BMDCs migrated more efficiently to peripheral lymph nodes in vivo. InsP4 deficient BMDCs also have enhanced secretion of pro-inflammatory cytokines/chemokines and mediate stronger antigen presentation to antigen-specific T cells. Our data support an important role for InsP4 in DC migration and cytokine secretion, identifying InsP4 as a dual regulator of Akt and ERK signaling pathways that controls DC function.
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Austin, R. Marshall. "Can regulatory proficiency testing by the cytobureaucracy decrease both false negatives and cervical cancer deaths?" Diagnostic Cytopathology 11, no. 2 (August 1994): 109–12. http://dx.doi.org/10.1002/dc.2840110202.
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Kowalczyk, Aleksandra, and Li Zhang. "B7-CTLA4 reverse signaling is responsible for regulatory T cell-induced suppression of dendritic cells (168.23)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 168.23. http://dx.doi.org/10.4049/jimmunol.186.supp.168.23.
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Abstract CD4+CD25+Foxp3+ regulatory T cells (Treg) are essential for maintaining immune tolerance and homeostasis. It has been shown that natural Treg can inhibit up-regulation of costimulatory molecules on dendritic cells (DC). However, the mechanism leading to this phenomenon has not been elucidated. Whether inducible Treg (iTreg) also possess this function has not been previously investigated. Here, we demonstrate that iTreg could inhibit LPS-induced DC maturation and mediate down-regulation of CD80 and CD86 on mature DC. This process is CTLA4-dependent as Treg isolated from CTLA4-/- mice did not down-modulate B7 molecules on DC. Furthermore, CTLA4Ig, but not CD28Ig, mimicked iTreg action. Down-regulation of CD80/CD86 was not due to endocytosis or protease-dependent shedding, but rather to a reverse signaling through B7. CTLA4Ig treatment decreased CD80 and CD86 transcription, as well as NFκB activity upon LPS stimulation. Interestingly, both CTLA4Ig and co-incubation with iTreg induced a profound STAT3 phosphorylation in DC, whereas no significant effect on the proximal NFκB pathway was observed. Inhibition of STAT3 activation partially abolished CTLA4Ig-induced CD80/CD86 down-modulation suggesting involvement of this molecule in the observed process. Our data reveal a novel signaling pathway by which Treg can suppress DC via reverse signaling, and may provide new opportunities for therapies targeting costimulatory pathways.
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Matta, Benjamin, Jeremy Lott, Lisa Mathews, Brian Rosborough, Bruce Blazar, and Heth Turnquist. "IL-33 stimulates dendritic cell secretion of IL-2 that promotes selective expansion of ST2+Foxp3+ regulatory T cells (IRC5P.460)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 125.9. http://dx.doi.org/10.4049/jimmunol.192.supp.125.9.
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Abstract IL-33 is a pleiotropic IL-1 family cytokine that signals via ST2 and expands ST2+Foxp3+ regulatory T cells (Treg) in vivo. As ST2+ Treg show poor expansion by direct IL-33 stimulation, we sought to define mechanisms mediating their expansion. IL-2 signaling promotes ST2 expression on CD4+ T cells, and dendritic cells (DC) express ST2 (able to respond to IL-33), and are a potential source of IL-2. Thus, we examined if IL-33 mediates ST2+ Treg expansion by stimulating DC IL-2 production. CD11c+ wild type (WT) or IL-2 knockout (KO) bone marrow DC were exposed to IL-33 or LPS. DC phenotype was evaluated by multi-color flow cytometric analysis. The influence of IL-33 DC on T cell function was evaluated in MLR with CD4+ T cells, and T cell proliferation and phenotype were determined by flow analysis. Cytokines were quantitated by ELISA. We found that unlike LPS, IL-33 does not influence DC surface phenotype or induce pro-inflammatory cytokine production compared to controls. However, IL-33 induces a 5-fold increase IL-2 production by DC. In MLR, IL-33 DC selectively expand an activated subset of ST2+Foxp3+ Treg that are CD44hiICOShi. IL-33 DC-derived IL-2 is critical since IL-33-exposed IL-2 KO DC fail to expand ST2+ Treg. In summary, IL-33 licenses DC to selectively expand a subset of activated Treg through production of IL-2, in the absence of classical DC activation. These findings may be harnessed to aid the development of novel therapeutics aimed at promoting immune tolerance.
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Lu, L., S. Qian, P. A. Hershberger, W. A. Rudert, D. H. Lynch, and A. W. Thomson. "Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation." Journal of Immunology 158, no. 12 (June 15, 1997): 5676–84. http://dx.doi.org/10.4049/jimmunol.158.12.5676.
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Abstract Activation of T cells is induced efficiently by dendritic cells (DC), but little is known about the role of DC in the regulation of T cell death. In this study, highly purified DC (DEC-205+, MHC class II(high), B7-1+ [CD80+], B7-2high [CD86high], CD40+, CD11c+) grown from normal mouse bone marrow in granulocyte-macrophage CSF + IL-4 were found to express FasL (CD95L) mRNA by reverse transcriptase PCR and to uniformly express FasL by both flow cytometric and immunocytochemical analyses. These cells, but not DC propagated from FasL-deficient (B6.gld) mice, induced dose-dependent increases in DNA fragmentation in Fas+ Jurkat T cells over 18 h coculture. Addition of mouse Fas-Fc fusion protein at the start of the cultures diminished this effect. Even at high relative concentrations, however, B7-2high DC induced only low levels of DNA fragmentation in Con A or alloactivated splenic T cells, as determined by radio- or spectrofluorometric assays and by in situ nick-end labeling. However, in the presence of CTLA4Ig, a molecule that blocks the B7-CD28 costimulatory pathway, DC that failed to stimulate in primary MLR induced markedly augmented levels of apoptosis in alloactivated T cells. CTLA4Ig treatment also increased the level of DNA fragmentation induced by FasL-deficient DC, indicating the existence of additional potential (Fas-independent) pathways of DC-induced T cell death. These findings suggest that the costimulatory (B7-CD28) and T cell death-inducing pathways may play important counter-regulatory roles in dictating the outcome of (allogeneic) DC-T cell interactions.
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Fodor, W. L., S. A. Rollins, E. R. Guilmette, E. Setter, and S. P. Squinto. "A novel bifunctional chimeric complement inhibitor that regulates C3 convertase and formation of the membrane attack complex." Journal of Immunology 155, no. 9 (November 1, 1995): 4135–38. http://dx.doi.org/10.4049/jimmunol.155.9.4135.
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Abstract Human cells express cell surface complement regulatory molecules that inhibit the activity of the C3/C5 convertases (DAF, MCP, CR1) or inhibit the membrane attack complex (CD59). A single molecule that inhibits both the convertase activity and formation of the membrane attack complex has never been characterized. To this end, we have developed two reciprocal chimeric complement inhibitors (CD, NH2-CD59-DAF-GPI; and DC, NH2-DAF-CD59-GPI) that contain the functional domains of decay accelerating factor (DAF; CD55) and CD59. Cell surface expression of the CD and DC chimeric proteins was detected with DAF- and CD59-specific antisera. Cell surface C3d deposition was inhibited on cells expressing the chimeric molecules, thereby indicating that the DAF moiety was functional in both molecules. Conversely, Ab-blocking experiments demonstrated that only the DC molecule retained CD59 function. Therefore, the DC molecule represents a novel potent chimeric bifunctional complement inhibitor that retains the functional domains of two distinct complement regulatory molecules.
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García-Vallejo, J. J., J. M. Ilarregui, H. Kalay, S. Chamorro, N. Koning, W. W. Unger, M. Ambrosini, et al. "CNS myelin induces regulatory functions of DC-SIGN–expressing, antigen-presenting cells via cognate interaction with MOG." Journal of Experimental Medicine 211, no. 7 (June 16, 2014): 1465–83. http://dx.doi.org/10.1084/jem.20122192.
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Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN–dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG–DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.
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Jayakumar, Asha, Michael J. Donovan, Vinita Tripathi, Marcelo Ramalho-Ortigao, and Mary Ann McDowell. "Leishmania major Infection Activates NF-κB and Interferon Regulatory Factors 1 and 8 in Human Dendritic Cells." Infection and Immunity 76, no. 5 (March 3, 2008): 2138–48. http://dx.doi.org/10.1128/iai.01252-07.
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ABSTRACT The salient feature of dendritic cells (DC) is the initiation of appropriate adaptive immune responses by discriminating between pathogens. Using a prototypic model of intracellular infection, we previously showed that Leishmania major parasites prime human DC for efficient interleukin-12 (IL-12) secretion. L. major infection is associated with self-limiting cutaneous disease and powerful immunity. In stark contrast, the causative agent of visceral leishmaniasis, Leishmania donovani, does not prime human DC for IL-12 production. Here, we report that DC priming by L. major infection results in the early activation of NF-κB transcription factors and the up-regulation and nuclear translocation of interferon regulatory factor 1 (IRF-1) and IRF-8. The inhibition of NF-κB activation by the pretreatment of DC with caffeic acid phenethyl ester blocks L. major-induced IRF-1 and IRF-8 activation and IL-12 expression. We further demonstrate that IRF-1 and IRF-8 obtained from L. major-infected human DC specifically bind to their consensus binding sites on the IL-12p35 promoter, indicating that L. major infection either directly stimulates a signaling cascade or induces an autocrine pathway that activates IRF-1 and IRF-8, ultimately resulting in IL-12 transcription.
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Akkaya, Billur, Munir Akkaya, Olena Kamenyeva, Juraj Kabat, David W. Dorward, Amanda H. Holstein, Mitra P. Maz, and Ethan M. Shevach. "Unique interaction dynamics and peptide-MHC class II (pMHC II) transendocytosis lead to antigen-specific T regulatory cell (Treg)-mediated suppression." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 80.8. http://dx.doi.org/10.4049/jimmunol.198.supp.80.8.
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Abstract Tregs can employ numerous mechanisms for inhibiting immune responses. Antigen-specific Tregs exhibit enhanced capacity to suppress compared to polyclonal Tregs, but unique suppressor mechanisms used by antigen-specific Tregs have not been elucidated. We first compared the interaction of antigen-specific induced Tregs (iTregs) and antigen-specific T effector cells with dendritic cells (DC) using scanning electron microscopy and intravital two-photon microscopy. Antigen-specific iTregs uniquely and rapidly formed dense clusters around DC suggesting that they may prevent the access of antigen-specific CD4+ T cells to the DC surface. In an adoptive transfer model, this rapid interaction was accompanied by a decreased ability of co-transferred naïve T cells to interact with the DCs as indicated by their failure to decrease their motility. More importantly, antigen-specific iTregs were found to specifically transendocytose cognate peptide-MHCII complexes from the DC surface to a greater extent than T effector cells resulting in diminished levels of antigen on the DC surface. Transmission electron microscopy of DC-Treg co-cultures showed that Tregs engulfed parts of DC processes as membrane invaginations within two hours and then internalized the p-MHCII complexes into endosomal vesicles. Taken together, these results indicate a two-step process by which antigen-specific Tregs inhibit antigen presentation. They rapidly and efficiently adhere to the DC surface and then deplete the pMHC II complexes from the DC resulting in potent suppression of the capacity of the DC to activate antigen-specific T cells.
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Kim, Young-June, and Hal E. Broxmeyer. "Phagocytosis May Be a Regulatory Mechanism for Myeloid Dendritic Cells to Terminate Type 1 CD8+ T Cells." Blood 114, no. 22 (November 20, 2009): 1654. http://dx.doi.org/10.1182/blood.v114.22.1654.1654.
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Abstract Abstract 1654 Poster Board I-680 CD8+ cytotoxic T cells are often ‘exhausted’ by programmed death-1 (PD-1) signaling, and subsequently the functions of these cells are terminated especially in a tumor environment or upon chronic HIV or HCV infection. Subsets of myeloid cells referred to as myeloid derived suppressor cells (MDSC) or regulatory dendritic cells (DCs) have been implicated in inducing exhaustion or termination of effector CD8+ T cells. To this end, we developed various myeloid-derived dendritic cell (DC) types in vitro from human CD14+ monocytes using M-CSF or GM-CSF in the presence of IL-4 with/without other cytokines, and characterized these DCs with respect to their capacity to induce PD-1 expression on and exhaustion of CD8+ T cells. We then assessed their impact on longevity of CD8+ T cells following coculture. Myeloid DCs developed in vitro with M-CSF and IL-4 for 5 days (referred to as M-DC) did not express ligand for PD-1 (PD-L1) nor did they induce PD-1 on CD8+ T cells. Thus, using M-DCs as starting cells, we sought determinant factors that could modulate M-DCs to express PD-L1 and thereby induce exhaustion of CD8+ T cells. In order to better monitor exhaustion processes, we incubated human peripheral CD8+ T cells for 5 days in the presence of IL-15, an important cytokine for maintaining viability, before coculture. M-DCs showed little impact on exhaustion or longevity of the CD8+ T cells. IL-10 converted M-DC into a distinct myeloid DC subset (referred to as M-DC/IL-10) with an ability to express PD-L1 as well as to induce PD-1 on cocultured CD8+ T cells. M-DC/IL-10 cells markedly suppressed proliferation of cocultured CD8+ T cells. M-DC/IL-10 cells were morphologically unique with many granules and filamentous structures around the cell periphery. These IL-10 effects on M-DC were completely abrogated in the presence of TNF-á. M-DC/IL-10 cells could be further differentiated into another myeloid DC subset in the presence of IFN-γ (referred to as M-DC/IL-10/IFN-γ) with an ability to express even higher levels of PD-L1 compared to M-DC/IL-10 cells. The most remarkable effect of M-DC/IL-10/IFN-γ cells on cocultured CD8+ T cells was a dramatic loss of CD8+ T cells. Light and confocal microscopic observations indicated that loss of CD8+ T cells was due to phagocytosis by M-DC/IL-10/IFN-γ cells. As IFN-γ, a type 1 cytokine which is induced in CD8+ T cells by IL-12 is essential for phagocytosis, we tested whether IL-12 treatment of CD8+ T cells could further enhance phagocytosis induced by M-DC/IL-10/IFN-γ cells. Indeed, IL-12 treatment greatly increased numbers of phagocytosed CD8+ T cells. In contrast, IL-4 treated CD8+ T cells became resistant to phagocytosis, suggesting IFN-γ producing (type1) CD8+ T cells may be primary target cells for the M-DC/IL-10 cells mediated phagocytosis. CD4+ T cells were not as susceptible as CD8+ T cells to phagocytosis. We failed to detect such phagocytic activity induced by prototype DCs generated with GM-CSF and IL-4. Phagocytic activity was not inhibited by various arginase-1 inhibitors suggesting that nitric oxide signaling may not mediate phagocytic activity. Neutralizing antibody to PD-L1 slightly but significantly lowered phagocytic activity suggesting that PD-L1/PD-1 interaction may be partially involved in this process. Myeloid DCs are thought to be immunogenic, actively inducing T cell immune responses. Our results demonstrate that myeloid DCs may play suppressive roles as well through induction of phagocytic activity, especially against IFN-γ producing CD8+ T cells. This may serve as a regulatory mechanism for type 1 CD8+ T cell immune responses in an IL-10 enriched microenvironment. Disclosures No relevant conflicts of interest to declare.
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Mullins, David W., and Matthew P. Alexander. "Cyclophosphamide preconditioning facilitates autoimmune vitiligo and enhanced antitumor efficacy following vaccination with activated dendritic cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 204.12. http://dx.doi.org/10.4049/jimmunol.198.supp.204.12.
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Abstract Cyclophosphamide (CTX) has been used as a lymphoablative conditioning agent to deplete regulatory T cells (Tregs) and enhance the efficacy of adoptive immune therapies. We initially investigated whether CTX conditioning could enhance the immunogenicity of melanoma Ag-pulsed dendritic cells (DC) in a murine model. CTX enhanced Ag-specific CD8+ T cell responses and control of SC-growing OVA+ melanoma following immunization with activated OVA257–265-pulsed DC; immunogenicity and tumor control were abrogated by reconstitution of Treg compartments. Unexpectedly, CTX-conditioned, DC-immunized animals developed significant vitiligo, despite the absence of exogenous melanocyte-specific Ag in the vaccine. CTX treatment or DC immunization alone failed to induce vitiligo. Injection of CTX-conditioned mice with MHC class II−/− DC, but not β2 microglobulin−/− DC, induced vitiligo regardless of exogenous Ag, suggesting that the induction of vitiligo may result from cross-presentation of endogenous melanocyte Ag in an environment of relaxed tolerance. Ab-mediated depletion of CD8 cells abrogated the vitiligo. These data suggest that CTX conditioning liberates class I-restricted melanocyte Ag for cross-presentation by activated DC to cognate CD8 cells, which in turn, achieve full activation and effector function in the absence of a normal regulatory environment. CTX conditioning may also open dermal compartments for increased effector T cell infiltration. Thus, CTX mediates multiple immunomodulatory mechanisms that may impact the future design of immunotherapy for melanoma.