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1
Alonso, Michael N., Michael T. Wong, Angela L. Zhang, Daniel Winer, Megan M. Suhoski, Lorna L. Tolentino, Juliana Gaitan, et al. "TH1, TH2, and TH17 cells instruct monocytes to differentiate into specialized dendritic cell subsets." Blood 118, no. 12 (September 22, 2011): 3311–20. http://dx.doi.org/10.1182/blood-2011-03-341065.
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Abstract Monocytes and T helper (TH) cells rapidly infiltrate inflamed tissues where monocytes differentiate into inflammatory dendritic cells (DCs) through undefined mechanisms. Our studies indicate that TH cells frequently interact with monocytes in inflamed skin and elicit the differentiation of specialized DC subsets characteristic of these lesions. In psoriasis lesions, TH1 and TH17 cells interact with monocytes and instruct these cells to differentiate into TH1- and TH17-promoting DCs, respectively. Correspondingly, in acute atopic dermatitis, TH2 cells interact with monocytes and elicit the formation of TH2-promoting DCs. DC formation requires GM-CSF and cell contact, whereas TH subset specific cytokines dictate DC function and the expression of DC subset specific surface molecules. Moreover, the phenotypes of T cell–induced DC subsets are maintained after subsequent stimulation with a panel of TLR agonists, suggesting that TH-derived signals outweigh downstream TLR signals in their influence on DC function. These findings indicate that TH cells govern the formation and function of specialized DC subsets.
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Ito, Tomoki, Ryuichi Amakawa, Tsuneyasu Kaisho, Hiroaki Hemmi, Kenichirou Tajima, Kazutaka Uehira, Yoshio Ozaki, Hideyuki Tomizawa, Shizuo Akira, and Shirou Fukuhara. "Interferon-α and Interleukin-12 Are Induced Differentially by Toll-like Receptor 7 Ligands in Human Blood Dendritic Cell Subsets." Journal of Experimental Medicine 195, no. 11 (May 28, 2002): 1507–12. http://dx.doi.org/10.1084/jem.20020207.
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Dendritic cells (DCs) play a crucial role in the immune responses against infections by sensing microbial invasion through toll-like receptors (TLRs). In humans, two distinct DC subsets, CD11c− plasmacytoid DCs (PDCs) and CD11c+ myeloid DCs (MDCs), have been identified and can respond to different TLR ligands, depending on the differential expression of cognate TLRs. In this study, we have examined the effect of TLR-7 ligands on human DC subsets. Both subsets expressed TLR-7 and could respond to TLR-7 ligands, which enhanced the survival of the subsets and upregulated the surface expression of costimulatory molecules such as CD40, CD80, and CD86. However, the cytokine induction pattern was distinct in that PDCs and MDCs produced interferon (IFN)-α and interleukin (IL)-12, respectively. In response to TLR-7 ligands, the Th1 cell supporting ability of both DC subsets was enhanced, depending on the cytokines the respective subsets produced. This study demonstrates that TLR-7 exerts its biological effect in a DC subset-specific manner.
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Ahmad, Sharon. "DC subsets do it differently." Nature Reviews Immunology 7, no. 2 (February 2007): 89. http://dx.doi.org/10.1038/nri2027.
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Girard, Melanie, Jaclyn C. Law, Maria I. Edilova, and Tania H. Watts. "Type I interferons drive the maturation of human DC3s with a distinct costimulatory profile characterized by high GITRL." Science Immunology 5, no. 53 (November 13, 2020): eabe0347. http://dx.doi.org/10.1126/sciimmunol.abe0347.
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Human mononuclear phagocytes comprise specialized subsets of dendritic cells (DCs) and monocytes, but how these subsets individually regulate expression of the molecular signals involved in T cell costimulation is incompletely understood. Here, we used multiparameter flow cytometry and CITE-sequencing to investigate the cell type–specific responses of human peripheral blood DC and monocyte subsets to type I interferons (IFN-I), focusing on differential regulation of costimulatory molecules. We report that IFN-β drives the maturation of the recently identified human CD1c+ CD5− DC3 subset into cells with higher GITRL and lower CD86 expression compared with other conventional DC subsets. Transcriptomic analysis confirmed that DC3s have an intermediate phenotype between that of CD1c+ CD5+ DC2s and CD14+ monocytes, characterized by high expression of MHCII, Fc receptors, and components of the phagocyte NADPH oxidase. IFN-β induced a shared core response in human DC and monocyte subsets as well as subset-specific responses, including differential expression of costimulatory molecules. Gene regulatory network analysis suggests that upon IFN-β stimulation NFKB1 drives DC3s to acquire a maturation program shared with DC2s. Accordingly, inhibition of NF-κB activation prevented the acquisition of a mature phenotype by DC3s upon IFN-β exposure. Collectively, this study provides insight into the cell type–specific response of human DC and monocyte subsets to IFN-I and highlights the distinct costimulatory potential of DC3s.
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Coates, P. Toby H., Simon M. Barratt-Boyes, Linyou Zhang, Vera S. Donnenberg, Peta J. O'Connell, Alison J. Logar, F. Jason Duncan, et al. "Dendritic cell subsets in blood and lymphoid tissue of rhesus monkeys and their mobilization with Flt3 ligand." Blood 102, no. 7 (October 1, 2003): 2513–21. http://dx.doi.org/10.1182/blood-2002-09-2929.
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Abstract We provide phenotypic and functional evidence of premonocytoid dendritic cells (DCs) and preplasmacytoid DCs in blood and of corresponding DC subsets in secondary lymphoid tissue of rhesus monkeys. Subsets were identified and sorted by 4-color flow cytometry using antihuman monoclonal antibodies cross-reactive with rhesus monkey. To mobilize pre-DC subsets, fms-like tyrosine 3 kinase ligand (Flt3L; 100 μg/kg subcutaneously) was administered for 10 days. Presumptive pre-DC subsets were identified within the lineage- (Lin-) major histocompatibility complex (MHC) class II+ fraction of blood mononuclear cells. Premonocytoid DCs were CD11c+CD123- (interleukin-3Rα- [IL-3Rα-]). Preplasmacytoid DCs were characterized as CD11c-CD123++ Flt3L increased the CD11c+ pre-DC (7-fold) and CD123++ pre-DC subsets (3-fold) in blood. The freshly isolated CD11c+ pre-DC subset induced modest proliferation of naive allogeneic T cells. After overnight culture with granulocyte macro-phage-colony-stimulating factor (GMCSF) and CD40L, both subsets up-regulated surface costimulatory molecules, and CD11c+ pre-DCs became potent allostimulators. Freshly isolated CD123++ pre-DCs showed typical plasmacytoid morphology and, when cultured with IL-3 and CD40L for 72 hours, developed mature DC morphology. Following stimulation with CD40L, CD11c+ pre-DCs secreted increased levels of IL-12p40. Importantly, herpes simplex virus-stimulated CD123++ pre-DCs, but not CD11c+ pre-DCs, secreted interferon-α (IFN-α). Corresponding DC subsets were identified by flow analysis and immunohistochemistry in lymph nodes wherein both populations were increased 2- to 3-fold by Flt3L administration. CD123+ pre-DCs produced IFN-α in response to in vivo viral infection. Thus, rhesus monkeys exhibit 2 distinct DC precursor populations that closely resemble those of humans. Both are mobilized into blood and lymphoid tissue by Flt3L, offering potential for their further characterization and possible therapeutic application. (Blood. 2003;102:2513-2521)
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Klebanoff, Christopher A., Sean P. Spencer, Parizad Torabi-Parizi, John R. Grainger, Rahul Roychoudhuri, Yun Ji, Madhusudhanan Sukumar, et al. "Retinoic acid controls the homeostasis of pre-cDC–derived splenic and intestinal dendritic cells." Journal of Experimental Medicine 210, no. 10 (September 2, 2013): 1961–76. http://dx.doi.org/10.1084/jem.20122508.
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Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)–derived splenic CD11b+CD8α−Esamhigh DCs and the developmentally related CD11b+CD103+ subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC–derived CD11b−CD8α+ and CD11b−CD103+ nor monocyte-derived CD11b+CD8α−Esamlow or CD11b+CD103− DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b+CD8α− subset, whereas transfer into vitamin A–deficient (VAD) hosts caused diversion to the CD11b−CD8α+ lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II–restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC–derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.
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Yin, Xiangyun, Shuting Chen, and Stephanie C. Eisenbarth. "Dendritic Cell Regulation of T Helper Cells." Annual Review of Immunology 39, no. 1 (April 26, 2021): 759–90. http://dx.doi.org/10.1146/annurev-immunol-101819-025146.
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As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.
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Segura, Elodie, Jenny Valladeau-Guilemond, Marie-Hélène Donnadieu, Xavier Sastre-Garau, Vassili Soumelis, and Sebastian Amigorena. "Characterization of resident and migratory dendritic cells in human lymph nodes." Journal of Experimental Medicine 209, no. 4 (March 19, 2012): 653–60. http://dx.doi.org/10.1084/jem.20111457.
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Dendritic cells (DCs) initiate adaptive immune responses in lymph nodes (LNs). In mice, LN DCs can be divided into resident and tissue-derived populations, the latter of which migrate from the peripheral tissues. In humans, different subsets of DCs have been identified in the blood, spleen, and skin, but less is known about populations of resident and migratory tissue-derived DCs in LNs. We have analyzed DCs in human LNs and identified two populations of resident DCs that are present in all LNs analyzed, as well as in the spleen and tonsil, and correspond to the two known blood DC subtypes. We also identify three main populations of skin-derived migratory DCs that are present only in skin-draining LNs and correspond to the DC subsets found in the skin. Resident DCs subsets induce both Th1 and Th2 cytokines in naive allogeneic T lymphocytes, whereas the corresponding blood subsets failed to induce efficient Th2 polarization. LN-resident DCs also cross-present antigen without in vitro activation, whereas blood DCs fail to do so. Among migratory DCs, one subset was poor at both CD4+ and CD8+ T cell activation, whereas the other subsets induced only Th2 polarization. We conclude that in humans, skin-draining LNs host both resident and migratory DC subsets with distinct functional abilities.
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Kerkhoff, Nathalie, Shahram Kordasti, Thomas Seidl, Arjan A. Van de Loosdrecht, and Ghulam J. Mufti. "Expansion of CD141int Dendritic Cells in Myelodysplastic Syndrome (MDS)." Blood 120, no. 21 (November 16, 2012): 3856. http://dx.doi.org/10.1182/blood.v120.21.3856.3856.
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Abstract Abstract 3856 Introduction Immunological responses play an important role in the pathogenesis and progression of myelodysplastic syndromes (MDS). Several studies have confirmed that immune dysregulation in MDS may play a critical role in the initiation and progression of the dysplastic clone. We have already shown the importance of expanded Tregs in high risk MDS and its reverse correlation with the number of Th17 cells in low risk disease. However, the potential role of dendritic cells (DCs) in this immune dysregulation and in the expansion of Tregs in MDS is not fully understood. DCs are professional antigen presenting cells (APCs) and potent stimulators of T cells through (cross-)presentation of antigens via MHC class I and II molecules to CD8+ cytotoxic T lymphocytes (CTL) and CD4+ T helper (Th) cells, respectively. DCs are also important in the development of specific anti-tumor T-cell responses. Some subtypes of DCs also play an important role in the expansion of regulatory T cells (Tregs) and induce immune-suppression and editing. There are 3 main subpopulations of DCs in human: plasmacytoid DCs (CD303+ cells) and two types of myeloid DCs (CD1c+ and CD141+ cells). The aim of this study was to investigate the frequency of different DC subsets in the bone marrow and peripheral blood of MDS patients. Patients and methods Twelve peripheral blood and 26 bone marrow samples from MDS patients and 11 peripheral blood and 4 bone marrow samples from healthy donors (HDs) were studied. Three different DC subsets were investigated by flow-cytometry: plasmacytoid DC (Lineage−, HLA-DR+, CD303+), myeloid DC 1 (Lineage−, HLA-DR+, CD1c+) and myeloid DC 2 (Lineage−, HLA-DR+, CD141hi). Results Decreased frequency of DCs in peripheral blood compared to BM Frequencies of all DC subsets were significantly lower in patients' peripheral blood compared to patients' bone marrow (CD1c+ DC 2.56×102 v 7.02×102 and 0.06% v 0.33%, p=0.001; CD141+ DC 4.18×103 v 6.04×103 and 0.44% v 2.44%, p=0.005; CD303+ DC 0.06×102 v 1.07×102 and 0.01% v 0.13%, p=0.045). DC subsets The percentage of the CD1c+ DC subset was significantly reduced in the peripheral blood of MDS patients compared to HD (1.46×103 v 0.26×103, 0.18% v 0.05%, p=0.001) (figure 1). Interestingly, we have noticed an additional subset of DCs, which was not described before. The definition of this subset was based on intermediate expression of CD141 compared to previously described myeloid DCs. The CD141int subset was the only DC subset that was increased in peripheral blood of MDS patients compared to HD (0.41×102 v 2.30×102, 0.01% v 0.13%, p=0.019). Both CD1c+ and CD141int DC subsets were increased in the bone marrow of MDS patients compared to healthy donors. However, these differences were not statistically significant. Discussion Although the decreased number of circulating DCs is reported in MDS, our data suggest that this decrease is more profound in the peripheral blood compared to BM. We have also shown that this decrease is mainly in CD1c+ myeloid DCs. In this study, we describe two subsets of CD141 DCs, CD141hi and CD141int. The CD141int subpopulation is the only DC subset that is increased in MDS patients compared to HD. Our data suggest that DCs from peripheral blood may migrate to the bone marrow in response to an aberrant BM microenvironment in MDS. Nevertheless, the pattern of decrease in DC numbers is not uniform and CD141int DCs are in fact increased. It is already known that CD141+ DCs, play an important role in the induction of Tregs in an IL-10 dependent manner. We have also reported an increased number of Tregs in high-risk MDS, which correlates, with higher risk of progression toward AML. Our data suggest that CD141+ DCs may play a role in the expansion of Tregs in MDS. However, the exact function of this subset of DCs in MDS and their effect on CD4+ T-cells polarization needs to be investigated in more details. Disclosures: No relevant conflicts of interest to declare.
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Dalod, Marc, Tanya Hamilton, Rachelle Salomon, Thais P. Salazar-Mather, Stanley C. Henry, John D. Hamilton, and Christine A. Biron. "Dendritic Cell Responses to Early Murine Cytomegalovirus Infection." Journal of Experimental Medicine 197, no. 7 (April 7, 2003): 885–98. http://dx.doi.org/10.1084/jem.20021522.
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Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.
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Patel, Vineet Indrajit, and Jordan Patrick Metcalf. "Identification and characterization of human dendritic cell subsets in the steady state: a review of our current knowledge." Journal of Investigative Medicine 64, no. 4 (March 8, 2016): 833–47. http://dx.doi.org/10.1136/jim-2016-000072.
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Dendritic cells (DC) are generally categorized as a group of rare antigen presenting cells that are to the crucial development of immune responses to pathogens and also of tolerance to self-antigens. Therefore, having the ability to identify DC in specific tissues and to test their functional abilities in the steady state are scientific gaps needing attention. Research on primary human DC is lacking due to their rarity and the difficulty of obtaining tissue samples. However, recent findings have shown that several different DC subsets exist, and that these subsets vary both by markers expressed and functions depending on their specific microenvironment. After discriminating from other cell types, DC can be split into myeloid and plasmacytoid fractions. While plasmacytoid DC express definite markers, CD123 and BDCA-2, myeloid DC encompass several different subsets with overlapping markers expressed. Such markers include the blood DC antigens BDCA-1 and BDCA-3, along with Langerin, CD1a and CD14. Marker specificity is further reduced when accounting for microenvironmental differences, as observed in the blood, primary lymphoid tissues, skin and lungs. The mixed leukocyte reaction (MLR) has been used to measure the strength of antigen presentation by specific DC subsets. Surface markers and MLR require standardization to enable consistent identification of and comparisons between DC subsets. To alleviate these issues, researchers have begun comparing DC subsets at the transcriptional level. This has allowed degrees of relatedness to be determined between DC in different microenvironments, and should be a continued area of focus in years to come.
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Welty, Nathan E., Christopher Staley, Nico Ghilardi, Michael J. Sadowsky, Botond Z. Igyártó, and Daniel H. Kaplan. "Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism." Journal of Experimental Medicine 210, no. 10 (September 9, 2013): 2011–24. http://dx.doi.org/10.1084/jem.20130728.
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Dendritic cells (DCs) in the intestinal lamina propria (LP) are composed of two CD103+ subsets that differ in CD11b expression. We report here that Langerin is expressed by human LP DCs and that transgenic human langerin drives expression in CD103+CD11b+ LP DCs in mice. This subset was ablated in huLangerin-DTA mice, resulting in reduced LP Th17 cells without affecting Th1 or T reg cells. Notably, cognate DC–T cell interactions were not required for Th17 development, as this response was intact in huLangerin-Cre I-Aβfl/fl mice. In contrast, responses to intestinal infection or flagellin administration were unaffected by the absence of CD103+CD11b+ DCs. huLangerin-DTA x BatF3−/− mice lacked both CD103+ LP DC subsets, resulting in defective gut homing and fewer LP T reg cells. Despite these defects in LP DCs and resident T cells, we did not observe alterations of intestinal microbial communities. Thus, CD103+ LP DC subsets control T cell homeostasis through both nonredundant and overlapping mechanisms.
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Iwasaki, Akiko, and Brian L. Kelsall. "Localization of Distinct Peyer's Patch Dendritic Cell Subsets and Their Recruitment by Chemokines Macrophage Inflammatory Protein (Mip)-3α, Mip-3β, and Secondary Lymphoid Organ Chemokine." Journal of Experimental Medicine 191, no. 8 (April 17, 2000): 1381–94. http://dx.doi.org/10.1084/jem.191.8.1381.
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We describe the anatomical localization of three distinct dendritic cell (DC) subsets in the murine Peyer's patch (PP) and explore the role of chemokines in their recruitment. By two-color in situ immunofluorescence, CD11b+ myeloid DCs were determined to be present in the subepithelial dome (SED) region, whereas CD8α+ lymphoid DCs are present in the T cell–rich interfollicular region (IFR). DCs that lack expression of CD8α or CD11b (double negative) are present in both the SED and IFR. By in situ hybridization, macrophage inflammatory protein (MIP)-3α mRNA was dramatically expressed only by the follicle-associated epithelium overlying the SED, while its receptor, CCR6, was concentrated in the SED. In contrast, CCR7 was expressed predominantly in the IFR. Consistent with these findings, reverse transcriptase polymerase chain reaction analysis and in vitro chemotaxis assays using freshly isolated DCs revealed that CCR6 was functionally expressed only by DC subsets present in the SED, while all subsets expressed functional CCR7. Moreover, none of the splenic DC subsets migrated toward MIP-3α. These data support a distinct role for MIP-3α/CCR6 in recruitment of CD11b+ DCs toward the mucosal surfaces and for MIP-3β/CCR7 in attraction of CD8α+ DCs to the T cell regions. Finally, we demonstrated that all DC subsets expressed an immature phenotype when freshly isolated and maintained expression of subset markers upon maturation in vitro. In contrast, CCR7 expression by myeloid PP DCs was enhanced with maturation in vitro. In addition, this subset disappeared from the SED and appeared in the IFR after microbial stimulation in vivo, suggesting that immature myeloid SED DCs capture antigens and migrate to IFR to initiate T cell responses after mucosal microbial infections.
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Docq, Molène, Mathias Vétillard, Carmen Gallego, Agnieszka Jaracz-Ros, Françoise Mercier-Nomé, Françoise Bachelerie, and Géraldine Schlecht-Louf. "Multi-Tissue Characterization of GILZ Expression in Dendritic Cell Subsets at Steady State and in Inflammatory Contexts." Cells 10, no. 11 (November 13, 2021): 3153. http://dx.doi.org/10.3390/cells10113153.
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Dendritic cells (DCs) are key players in the control of tolerance and immunity. Glucocorticoids (GCs) are known to regulate DC function by promoting their tolerogenic differentiation through the induction of inhibitory ligands, cytokines, and enzymes. The GC-induced effects in DCs were shown to critically depend on increased expression of the Glucocorticoid-Induced Leucine Zipper protein (GILZ). GILZ expression levels were further shown to control antigen-presenting cell function, as well as T-cell priming capacity of DCs. However, the pattern of GILZ expression in DC subsets across tissues remains poorly described, as well as the modulation of its expression levels in different pathological settings. To fill in this knowledge gap, we conducted an exhaustive analysis of GILZ relative expression levels in DC subsets from various tissues using multiparametric flow cytometry. This study was performed at steady state, in the context of acute as well as chronic skin inflammation, and in a model of cancer. Our results show the heterogeneity of GILZ expression among DC subsets as well as the complexity of its modulation, that varies in a cell subset- and context-specific manner. Considering the contribution of GILZ in the control of DC functions and its potential as an immune checkpoint in cancer settings, these results are of high relevance for optimal GILZ targeting in therapeutic strategies.
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Kaminsky, Lauren W., Janet J. Sei, Nikhil J. Parekh, Michael L. Davies, Irene E. Reider, Tracy E. Krouse, and Christopher C. Norbury. "Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection." Journal of Virology 89, no. 19 (July 22, 2015): 9974–85. http://dx.doi.org/10.1128/jvi.01024-15.
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ABSTRACTViruses that spread systemically from a peripheral site of infection cause morbidity and mortality in the human population. Innate myeloid cells, including monocytes, macrophages, monocyte-derived dendritic cells (mo-DC), and dendritic cells (DC), respond early during viral infection to control viral replication, reducing virus spread from the peripheral site. Ectromelia virus (ECTV), an orthopoxvirus that naturally infects the mouse, spreads systemically from the peripheral site of infection and results in death of susceptible mice. While phagocytic cells have a requisite role in the response to ECTV, the requirement for individual myeloid cell populations during acute immune responses to peripheral viral infection is unclear. In this study, a variety of myeloid-specific depletion methods were used to dissect the roles of individual myeloid cell subsets in the survival of ECTV infection. We showed that DC are the primary producers of type I interferons (T1-IFN), requisite cytokines for survival, following ECTV infection. DC, but not macrophages, monocytes, or granulocytes, were required for control of the virus and survival of mice following ECTV infection. Depletion of either plasmacytoid DC (pDC) alone or the lymphoid-resident DC subset (CD8α+DC) alone did not confer lethal susceptibility to ECTV. However, the function of at least one of the pDC or CD8α+DC subsets is required for survival of ECTV infection, as mice depleted of both populations were susceptible to ECTV challenge. The presence of at least one of these DC subsets is sufficient for cytokine production that reduces ECTV replication and virus spread, facilitating survival following infection.IMPORTANCEPrior to the eradication of variola virus, the orthopoxvirus that causes smallpox, one-third of infected people succumbed to the disease. Following successful eradication of smallpox, vaccination rates with the smallpox vaccine have significantly dropped. There is now an increasing incidence of zoonotic orthopoxvirus infections for which there are no effective treatments. Moreover, the safety of the smallpox vaccine is of great concern, as complications may arise, resulting in morbidity. Like many viruses that cause significant human diseases, orthopoxviruses spread from a peripheral site of infection to become systemic. This study elucidates the early requirement for innate immune cells in controlling a peripheral infection with ECTV, the causative agent of mousepox. We report that there is redundancy in the function of two innate immune cell subsets in controlling virus spread early during infection. The viral control mediated by these cell subsets presents a potential target for therapies and rational vaccine design.
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Lukens, Michaël V., Debby Kruijsen, Frank E. J. Coenjaerts, Jan L. L. Kimpen, and Grada M. van Bleek. "Respiratory Syncytial Virus-Induced Activation and Migration of Respiratory Dendritic Cells and Subsequent Antigen Presentation in the Lung-Draining Lymph Node." Journal of Virology 83, no. 14 (May 6, 2009): 7235–43. http://dx.doi.org/10.1128/jvi.00452-09.
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ABSTRACT In the respiratory tract, different dendritic cell (DC) populations guard a tight balance between tolerance and immunity to infectious or harmless materials to which the airways are continuously exposed. For infectious and noninfectious antigens administered via different routes, different subsets of DC might contribute during the induction of T-cell tolerance and immunity. We studied the impact of primary respiratory syncytial virus (RSV) infection on respiratory DC composition in C57BL/6 mice. We also tracked the migration of respiratory DC to the lymph nodes and studied antigen presentation by lung-derived and lymph node-resident DC to CD4+ and CD8+ T cells. We observed a massive influx of mainly CD103− CD11bhigh CD11c+ conventional DC (cDC) and plasmacytoid DC during the first 7 days of RSV infection, while CD103+ CD11blow CD11c+ cDC disappeared from the lung. The two major subsets of lung tissue DC, CD103+ CD11blow CD11c+ and CD103− CD11bhigh CD11c+ cDC, both transported RSV RNA to the lung-draining lymph node. Furthermore, these lung-derived cDC subsets as well as resident LN DC, which did not contain viral RNA, displayed viral antigen by major histocompatibility complex class I and class II to CD8+ and CD4+ T cells. Taken together, our data indicate that during RSV infections, at least three DC subsets might be involved during the activation of lymph node-homing naïve and memory CD4+ and CD8+ T cells.
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Kassianos, Andrew J., Xiangju Wang, Sandeep Sampangi, Kimberly Muczynski, Helen Healy, and Ray Wilkinson. "Increased tubulointerstitial recruitment of human CD141hi CLEC9A+ and CD1c+ myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease." American Journal of Physiology-Renal Physiology 305, no. 10 (November 15, 2013): F1391—F1401. http://dx.doi.org/10.1152/ajprenal.00318.2013.
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Dendritic cells (DCs) play critical roles in immune-mediated kidney diseases. Little is known, however, about DC subsets in human chronic kidney disease, with previous studies restricted to a limited set of pathologies and to using immunohistochemical methods. In this study, we developed novel protocols for extracting renal DC subsets from diseased human kidneys and identified, enumerated, and phenotyped them by multicolor flow cytometry. We detected significantly greater numbers of total DCs as well as CD141hi and CD1c+ myeloid DC (mDCs) subsets in diseased biopsies with interstitial fibrosis than diseased biopsies without fibrosis or healthy kidney tissue. In contrast, plasmacytoid DC numbers were significantly higher in the fibrotic group compared with healthy tissue only. Numbers of all DC subsets correlated with loss of kidney function, recorded as estimated glomerular filtration rate. CD141hi DCs expressed C-type lectin domain family 9 member A (CLEC9A), whereas the majority of CD1c+ DCs lacked the expression of CD1a and DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), suggesting these mDC subsets may be circulating CD141hi and CD1c+ blood DCs infiltrating kidney tissue. Our analysis revealed CLEC9A+ and CD1c+ cells were restricted to the tubulointerstitium. Notably, DC expression of the costimulatory and maturation molecule CD86 was significantly increased in both diseased cohorts compared with healthy tissue. Transforming growth factor-β levels in dissociated tissue supernatants were significantly elevated in diseased biopsies with fibrosis compared with nonfibrotic biopsies, with mDCs identified as a major source of this profibrotic cytokine. Collectively, our data indicate that activated mDC subsets, likely recruited into the tubulointerstitium, are positioned to play a role in the development of fibrosis and, thus, progression to chronic kidney disease.
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Briseño, Carlos G., Ansuman T. Satpathy, Jesse T. Davidson, Stephen T. Ferris, Vivek Durai, Prachi Bagadia, Kevin W. O’Connor, Derek J. Theisen, Theresa L. Murphy, and Kenneth M. Murphy. "Notch2-dependent DC2s mediate splenic germinal center responses." Proceedings of the National Academy of Sciences 115, no. 42 (October 2, 2018): 10726–31. http://dx.doi.org/10.1073/pnas.1809925115.
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CD4+ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes. This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2. Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation of MHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.
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van Pul, Kim M., Ronald J. C. L. M. Vuylsteke, Monique T. A. de Beijer, Rieneke van de Ven, M. Petrousjka van den Tol, Hein B. A. C. Stockmann, and Tanja D. de Gruijl. "Breast cancer-induced immune suppression in the sentinel lymph node is effectively countered by CpG-B in conjunction with inhibition of the JAK2/STAT3 pathway." Journal for ImmunoTherapy of Cancer 8, no. 2 (October 2020): e000761. http://dx.doi.org/10.1136/jitc-2020-000761.
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BackgroundWe previously showed selectively hampered activation of lymph node-resident (LNR) dendritic cell (DC) subsets in the breast cancer (BrC) sentinel lymph node (SLN) to precede a state of profound T cell anergy. Reactivating these DC subsets by intratumoral delivery of the Toll-like receptor-9 (TLR9) agonist CpG-B could potentially offer a promising immune therapeutic strategy to combat this immune suppression and prevent disease spread. Unfortunately, CpG-B can limit its own immune stimulatory activity through direct TLR9-mediated activation of signal transducer and activator of transcription 3 (STAT3), pinpointed as a key regulator of immune suppression in the tumor microenvironment. Here, we have investigated whether in vitro exposure to CpG-B, with or without simultaneous inhibition of STAT3 signaling, could overcome immune suppression in BrC SLN.MethodsImmune modulatory effects of CpG-B (CPG7909) with or without the JAK2/STAT3 inhibitor (STAT3i) AG490 were assessed in ex vivo cultured BrC SLN-derived single-cell suspensions (N=29). Multiparameter flow cytometric analyses were conducted for DC and T cell subset characterization and assessment of (intracellular) cytokine profiles. T cell reactivity against the BrC-associated antigen Mammaglobin-A was determined by means of interferon-γ ELISPOT assay.ResultsAlthough CpG-B alone induced activation of all DC subsets, combined inhibition of the JAK2/STAT3 pathway resulted in superior DC maturation (ie, increased CD83 expression), with most profound activation and maturation of LNR DC subsets. Furthermore, combined CpG-B and JAK2/STAT3 inhibition promoted Th1 skewing by counterbalancing the CpG-induced Th2/regulatory T cell response and significantly enhanced Mammaglobin-A specific T cell reactivity.ConclusionEx vivo immune modulation of the SLN by CpG-B and simultaneous JAK2/STAT3 inhibition can effectively overcome BrC-induced immune suppression by preferential activation of LNR DC, ultimately restoring type 1-mediated antitumor immunity, thereby securing a BrC-specific T cell response. These findings provide a clear rationale for clinical exploration of SLN-immune potentiation through local CpG/STAT3i administration in patients with BrC.
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Villadangos, Jose A., and Ken Shortman. "Found in translation: the human equivalent of mouse CD8+ dendritic cells." Journal of Experimental Medicine 207, no. 6 (May 31, 2010): 1131–34. http://dx.doi.org/10.1084/jem.20100985.
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The murine dendritic cell network comprises multiple subsets with distinct functions, but few of their human counterparts have been described. New data now reveals the likely human equivalent of the mouse DC subset specialized in cross-presentation.
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Aliberti, Julio, Oliver Schulz, Daniel J. Pennington, Hideki Tsujimura, Caetano Reis e Sousa, Keiko Ozato, and Alan Sher. "Essential role for ICSBP in the in vivo development of murine CD8α+ dendritic cells." Blood 101, no. 1 (January 1, 2003): 305–10. http://dx.doi.org/10.1182/blood-2002-04-1088.
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Abstract Interferon (IFN) consensus sequence-binding protein (ICSBP) is an important transcription factor regulating proinflammatory cytokine production and the development of mononuclear phagocytes in vitro. Here we analyzed the role of ICSBP in the in vivo differentiation of 3 major subsets of murine dendritic cells (DCs). We found that ICSBP is predominantly expressed by the CD8α+ subset, and more important, that ICSBP−/− mice have a profound and selective deficiency in CD8α+ DEC205+ DCs in lymphoid tissues. Studies using wild-type/ICSBP−/−chimeras revealed that this defect in CD8α+ DC development is intrinsic to bone marrow–derived progenitors and not dependent on ICSBP expression in the nonhemopoietic compartment. Because DC precursor frequencies are unaltered in the bone marrow of ICSBP−/− mice, ICSBP appears to function by regulating CD8α+ DC differentiation downstream from the generation of common DC progenitors. Although CD8α− DCs are present in normal numbers in ICSBP−/− animals, up-regulation of CD40, CD80, and major histocompatibility complex (MHC) class II expression was found to be impaired in this subset after in vivo microbial stimulation. Together these results demonstrate that ICSBP is critically required for the in vivo differentiation of CD8α+ DCs and may also influence the functional maturation of the CD8α− subsets.
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Teirlinck, Anne C., Meta Roestenberg, Else M. Bijker, Stephen L. Hoffman, Robert W. Sauerwein, and Anja Scholzen. "Plasmodium falciparum Infection of Human Volunteers Activates Monocytes and CD16+Dendritic Cells and Induces Upregulation of CD16 and CD1c Expression." Infection and Immunity 83, no. 9 (July 13, 2015): 3732–39. http://dx.doi.org/10.1128/iai.00473-15.
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Antigen-presenting cells (APCs) are key players in the induction and regulation of immune responses. InPlasmodium falciparummalaria, determination of which cells and pathways are activated in the network of APCs remains elusive. We therefore investigated the effects of a controlled human malaria infection in healthy, malaria-naive volunteers on the subset composition and activation status of dendritic cells (DCs) and monocytes. While subsets of monocytes increased in frequency during blood-stage infection, DC frequencies remained largely stable. Activation markers classically associated with peptide presentation to and priming of αβT cells, HLA-DR and CD86, were upregulated in monocytes and inflammatory CD16 myeloid DCs (mDCs) but not in the classical CD1c, BDCA2, or BDCA3 DC subsets. In addition, these activated APC subsets showed increased expression of CD1c, which is involved in glycolipid antigen presentation, and of the immune complex binding Fcγ receptor III (CD16). Our data show thatP. falciparumasexual parasites do not activate classical DC subsets but instead activate mainly monocytes and inflammatory CD16 mDCs and appear to prime alternative activation pathways via induction of CD16 and/or CD1c. Changes in expression of these surface molecules might increase antigen capture and enhance glycolipid antigen presentation in addition to the classical major histocompatibility complex class II (MHC-II) peptide presentation and thereby contribute to the initiation of T-cell responses in malaria. (This study has been registered at Clinicaltrials.gov under registration no. NCT01086917.)
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Carrington, Emma M., Jian-Guo Zhang, Robyn M. Sutherland, Ingela B. Vikstrom, Jamie L. Brady, Priscilla Soo, David Vremec, et al. "Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells." Proceedings of the National Academy of Sciences 112, no. 13 (March 16, 2015): 4044–49. http://dx.doi.org/10.1073/pnas.1417620112.
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Dendritic cells (DCs) are heterogeneous, comprising subsets with functional specializations that play distinct roles in immunity as well as immunopathology. We investigated the molecular control of cell survival of two main DC subsets: plasmacytoid DCs (pDCs) and conventional DCs (cDCs) and their dependence on individual antiapoptotic BCL-2 family members. Compared with cDCs, pDCs had higher expression of BCL-2, lower A1, and similar levels of MCL-1 and BCL-XL. Transgenic overexpression of BCL-2 increased the pDC pool size in vivo with only minor impact on cDCs. With a view to immune intervention, we tested BCL-2 inhibitors and found that ABT-199 (the BCL-2 specific inhibitor) selectively killed pDCs but not cDCs. Conversely, genetic knockdown of A1 profoundly reduced the proportion of cDCs but not pDCs. We also found that conditional ablation of MCL-1 significantly reduced the size of both DC populations in mice and impeded DC-mediated immune responses. Thus, we revealed that the two DC types have different cell survival requirements. The molecular basis of survival of different DC subsets thus advocates the antagonism of selective BCL-2 family members for treating diseases pertaining to distinct DC subsets.
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Hao, Xueli, Taeg S. Kim, and Thomas J. Braciale. "Differential Response of Respiratory Dendritic Cell Subsets to Influenza Virus Infection." Journal of Virology 82, no. 10 (March 19, 2008): 4908–19. http://dx.doi.org/10.1128/jvi.02367-07.
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ABSTRACT Dendritic cells (DC) are believed to play an important role in the initiation of innate and adaptive immune responses to infection, including respiratory tract infections, where respiratory DC (RDC) perform this role. In this report, we examined the susceptibilities of isolated murine RDC to influenza virus infection in vitro and the effect of the multiplicity of infection (MOI) on costimulatory ligand upregulation and inflammatory cytokine/chemokine production after infection. We found that the efficiency of influenza virus infection of RDC increased with increasing MOIs. Furthermore, distinct subpopulations of RDC differed in their susceptibilities to influenza virus infection and in the magnitude/tempo of costimulatory ligand expression. Additional characterization of the CD11c-positive (CD11c+) RDC revealed that the identifiable subsets of RDC differed in susceptibility to infection, with CD11c+ CD103+ DC exhibiting the greatest susceptibility, CD11c+ CD11bhi DC exhibiting intermediate susceptibility, and CD11c+ B220+ plasmacytoid DC (pDC) exhibiting the least susceptibility to infection. A companion analysis of the in vivo susceptibilities of these RDC subsets to influenza virus revealed a corresponding infection pattern. The three RDC subsets displayed different patterns of cytokine/chemokine production in response to influenza virus infection in vitro: pDC were the predominant producers of most cytokines examined, while CD103+ DC and CD11bhi DC produced elevated levels of the murine chemokine CXCL1 (KC), interleukin 12p40, and RANTES in response to influenza virus infection. Our results indicate that RDC are targets of influenza virus infection and that distinct RDC subsets differ in their susceptibilities and responses to infection.
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Li, Jian-Ming, Cynthia Giver, Doug McMillan, Wayne Harris, David L. Jaye, and Ned Waller. "Donor DC Subsets Polarize Donor T-Cell Immune Responses in Allogeneic BMT." Blood 106, no. 11 (November 16, 2005): 573. http://dx.doi.org/10.1182/blood.v106.11.573.573.
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Abstract Introduction: Impaired or inappropriate immune reconstitution after allogeneic bone marrow transplantation (BMT) can lead to infection, graft-versus-host disease (GvHD) and leukemia relapse. We have previously reported that BM contains two populations of dendritic cell (DC) subsets, CD11b+ DC and CD11b− DC, and that CD11b depleted donor BM promoted increased donor T-cell chimerism and increased graft-versus-leukemia (GvL) activity in C57BL/6 → B10BR transplants [BBMT, 2004, 10: 540]. To explore the mechanism by which CD11b-depletion improved allo-reactivity, we performed allogeneic hematopoietic cell transplants using defined populations of donor stem cells, DCs, and T-cells in a MHC mis-matched BMT model. Methods: We transplanted FACS purified populations of 50,000 GFP+ CD11b- DC or CD11b+ DC in combination with 5,000 FACS purified Lin- Sca-1+ c-kit+ hematopoietic stem cells (HSC) and 300,000 or 1,000,000 congenic spleen T-cells from C57BL/6 donors into C57BL/6[H-2Kb], B10BR[H-2Kk] and PL/J[H-2Ku] recipients. Proliferation of CFSE stained donor T-cells was measured at 72 hours post-transplant. FACS cytometric bead array and intracellular cytokine staining measured serum and intracellular cytokines in donor T-cells. Results: The initial proliferation and Ki-67 expression of CFSE labeled donor T-cells in allogeneic recipients were much higher than in syngeneic recipients (homeostatic proliferation). Confocal microscopy showed co-localization of donor DC subsets with donor T-cells in the recipient spleens at 3 and 10 days post-transplant. In the allogeneic transplant settings, donor T-cells co-transplanted with CD11b- DC showed increased IFN-γ synthesis at 3 and 10 days post-transplant compared to donor T-cells co-transplanted with HSC plus CD11b+ DC or HSC alone. Increased proliferation of donor T-cells led to increased donor T-cell chimerism at day 10, 30, 60, and day105 post-transplant among recipients of CD11b- DC compared to recipients of HSC alone or HSC plus CD11b+ DC (Figure 1). Transplantation of spleen T-cells and CD11b- DC did not increase GvHD, but was associated with full donor chimerism. In contrast, transplantation of allogeneic CD11b+ DC led to persistence and expansion of residual host T-cells (Figure 2), increased numbers of donor CD4+CD25++Foxp3+ T-cells, and higher serum level of IL-10 supporting early post-transplant expansion of donor T regulatory cells (Treg). Conclusions: Donor CD11b- DC promoted immune reconstitution by polarizing donor T-cells to Th1 immune responses associated with increased IFN-γ synthesis and donor T-cell proliferation, while donor CD11b+ DC suppressed immune reconstitution by inhibiting donor T-cell allogeneic immune responses. These data support a novel paradigm for the regulation of post-transplant immunity and suggest clinical methods to test the hypothesis that manipulation of the DC content of a hematopoietic cell allograft regulates post transplant immunity in the clinical setting. Figure 1. Donor Spleen Derived T-cells in Peripheral Blood [* p<0.05, v.s. recipients of HSC plus CD11b(+)DC and spleen T-cells] Figure 1. Donor Spleen Derived T-cells in Peripheral Blood [* p<0.05, v.s. recipients of HSC plus CD11b(+)DC and spleen T-cells] Figure 2. Host Derived T-cells in Peripheral Blood [* p<0.05, v.s. recipients of HSC plus CD11b(-)DC and spleen T-cells] Figure 2. Host Derived T-cells in Peripheral Blood [* p<0.05, v.s. recipients of HSC plus CD11b(-)DC and spleen T-cells]
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Lambotin, Mélanie, Thomas F. Baumert, and Heidi Barth. "Distinct Intracellular Trafficking of Hepatitis C Virus in Myeloid and Plasmacytoid Dendritic Cells." Journal of Virology 84, no. 17 (June 23, 2010): 8964–69. http://dx.doi.org/10.1128/jvi.00517-10.
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ABSTRACT Dendritic cells (DCs) are of pivotal importance for the initiation of immune responses to control and eliminate viral infections. The molecular mechanisms of hepatitis C virus (HCV) antigen uptake and processing by blood DCs are poorly defined. Here we show that human blood DC subsets acquire HCV independent of the classical HCV entry factors. Following HCV uptake, human plasmacytoid and myeloid DC subsets deliver HCV antigen into distinct endocytotic compartments, which are dedicated to presentation to CD4+ or CD8+ T cells. Our findings support a model of HCV antigen processing and presentation in which DC subsets fulfill distinct functions.
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Shahin, Kifah, Mary M. Sartor, Derek NJ Hart, and Kenneth F. Bradstock. "Upregulation of the Chemokine Receptor CCR5 on CD16+ Myeloid Blood Dendritic Cells in Allogeneic Hemopoietic Cell Transplant Patients Predicts for Acute Graft Versus Host Disease." Blood 118, no. 21 (November 18, 2011): 1982. http://dx.doi.org/10.1182/blood.v118.21.1982.1982.
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Abstract Abstract 1982 Introduction: Dendritic cells (DC) are centrally involved in the development of acute graft-versus-host disease (GvHD) following allogeneic hemopoietic cell transplantation (alloHCT). We previously showed that the activation status, as assessed by CMRF-44 antigen expression, of CD11c+ myeloid blood DC is highly associated with the onset and severity of acute GvHD (Transplantation. 2007;83:839–846). We also reported a positive correlation between acute GvHD and the expression of the chemokine receptor CCR5 on CD11c+ myeloid DC (Blood. 2009;114 Suppl.:2251). Given the phenotypic and functional heterogeneity of the CD11c+ DC population, we investigated CCR5 expression on the CD11c+ DC subsets and then monitored the informative CD11c+ CD16+ DC subset expression of CCR5 in the peripheral blood of 42 patients post alloHCT, and correlated the findings with GvHD. Methods: Peripheral blood was collected twice weekly up to Day 100 post transplant from 42 alloHCT patients. The expression of CCR5 receptor on CD11c+ and CD11c- DC subsets was evaluated using multiparameter flow cytometry. Results: Only the CD11c+ CD16+ DC subset lacked CCR5 and induced it upon alloactivation. Seventeen of 42 patients developed acute GvHD (5 grade I, 12 grades II-IV). The percentage of CD11c+ CD16+ DC expressing CCR5 correlated with the development of acute GvHD grades II-IV. The maximum CCR5 expression detected on CD11c+ CD16+ DC in patients prior to developing grades II-IV GvHD (mean 22.7 ± 4.3%, n=12) was higher than in those with grades 0-I GvHD (11.4 ± 1.7%, n=30) (p=0.0285). CCR5 levels >20% on CD16+ myeloid DC predicted grades II-IV GvHD with a sensitivity of 66.7% and specificity of 86.7%. Levels of expression of CCR5 on the CD11c+ CD16- DC and CD123+ plasmacytoid DC were not predictive of GvHD. Conclusion: Expression of CCR5 on circulating CD11c+ CD16+ myeloid DC post alloHCT correlated with the development of moderate to severe GvHD. This observation may reflect DC activation or altered DC homing during the alloimmune response. Detection of increased CCR5+ CD11c+ CD16+ DC may allow pre-emptive therapeutic intervention prior to the clinical diagnosis of GvHD. Disclosures: No relevant conflicts of interest to declare.
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Levenga, Henriette, Rob Woestenenk, Antonius V. M. B. Schattenberg, Frans Maas, Joop H. Jansen, Reinier Raymakers, Pieter H. M. De Mulder, Nicolaas Schaap, T. M. de Witte, and Harry Dolstra. "The Balance in Chimerism between T Cells and Blood Dendritic Cells in Relapsed CML Patients Influences the Induction of Alloreactivity Following Donor Lymphocyte Infusion." Blood 108, no. 11 (November 16, 2006): 5139. http://dx.doi.org/10.1182/blood.v108.11.5139.5139.
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Abstract Donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation induce complete remissions in 70 to 80% of patients with relapsed CML in chronic phase, but some patients do not respond sufficiently to DLI. We studied chimerism in subsets of immune cells in relation to the induction of alloreactivity. T cells and two subsets of DC (blood precursor myeloid dendritic cells [MDC] and blood precursor plasmacytoid dendritic cells [PDC]) were isolated from 15 relapsed CML-patients shortly before DLI for chimerism analysis. Furthermore, the absolute blood counts of DC-subsets were determined. Based on chimerism we identified three groups. Group 1 (4 patients) was complete donor chimeric in T cells and DC-subsets. These patients had an early stage of relapse and 3 of 4 patients attained a complete molecular remission (mCR) without significant GVHD. Group 2 (6 patients) was complete donor in T cells and mixed chimeric in DC-subsets. Median percentage of recipient MDC in 4 patients with mixed chimerism was 67% (range, 36%–72%). One patient was complete donor and one patient complete recipient chimeric in MDC. Median percentage of recipient PDC was 37% (range, 18%–58%) in 5 patients with mixed chimerism and in 1 patient PDC were complete recipient derived. All patients entered mCR, however in combination with GVHD in 4 and bone marrow hypoplasia in 3 patients. Group 3 (5 patients) had mixed chimerism in T cells and complete recipient chimerism in MDC in 4 of 5 patients. Only 2 patients entered mCR. Absolute DC numbers at the time of DLI did not predict the induction of an allo-immune response, however very low numbers of MDC and PDC were associated with progressive disease and a poor outcome. The combination of donor chimerism in T cells and mixed chimerism in DC-subsets in advanced relapse is associated with the most potent GVL effect following DLI. GVL and GVHD are separated in patients with an early relapse and donor chimerism in both T cells and DC-subsets. Finally, absolute DC numbers do not predict the strength of the alloresponse.
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Lamendour, Lucille, Nora Deluce-Kakwata-Nkor, Caroline Mouline, Valérie Gouilleux-Gruart, and Florence Velge-Roussel. "Tethering Innate Surface Receptors on Dendritic Cells: A New Avenue for Immune Tolerance Induction?" International Journal of Molecular Sciences 21, no. 15 (July 24, 2020): 5259. http://dx.doi.org/10.3390/ijms21155259.
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Dendritic cells (DCs) play a key role in immunity and are highly potent at presenting antigens and orienting the immune response. Depending on the environmental signals, DCs could turn the immune response toward immunity or immune tolerance. Several subsets of DCs have been described, with each expressing various surface receptors and all participating in DC-associated immune functions according to their specific skills. DC subsets could also contribute to the vicious circle of inflammation in immune diseases and establishment of immune tolerance in cancer. They appear to be appropriate targets in the control of inflammatory diseases or regulation of autoimmune responses. For all these reasons, in situ DC targeting with therapeutic antibodies seems to be a suitable way of modulating the entire immune system. At present, the field of antibody-based therapies has mainly been developed in oncology, but it is undergoing remarkable expansion thanks to a wide variety of antibody formats and their related functions. Moreover, current knowledge of DC biology may open new avenues for targeting and modulating the different DC subsets. Based on an update of pathogen recognition receptor expression profiles in human DC subsets, this review evaluates the possibility of inducing tolerant DCs using antibody-based therapeutic agents.
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Gao, Ming, Yan Yang, Daling Li, Bingxia Ming, Huoying Chen, Yan Sun, Yifan Xiao, et al. "CD27 natural killer cell subsets play different roles during the pre-onset stage of experimental autoimmune encephalomyelitis." Innate Immunity 22, no. 6 (July 9, 2016): 395–404. http://dx.doi.org/10.1177/1753425916658111.
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NK cells participate in the development of human multiple sclerosis (MS) and mouse experimental autoimmune encephalomyelitis (EAE), but the roles of different NK cell subsets in disease onset remain poorly understood. In this study, murine NK cells were divided into CD27high and CD27low/− subsets. The CD27high subset was decreased and the CD27low/− subset was increased in lymphoid organs during the pre-onset stage of EAE. Compared with the counterpart in naïve mice, the CD27high subset showed lower expression of Ly49D, Ly49H and NKG2D, and less production of IFN-γ, whereas the CD27low/− subset showed similar expression of the above mentioned surface receptors but higher cytotoxic activity in EAE mice. Compared with the CD27high subset, the CD27low/− subset exhibited increased promotion of DC maturation and no significant inhibition of T cells proliferation and Th17 cells differentiation in vitro. Additionally, adoptive transfer of the CD27low/− subset, but not the CD27high subset, exacerbated the severity of EAE. Collectively, our data suggest the CD27 NK cell subsets play different roles in controlling EAE onset, which provide a new understanding for the regulation of NK cell subsets in early autoimmune disease.
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Soares, Helena, HaeNa Waechter, Nicholas Glaichenhaus, Evelyne Mougneau, Hideo Yagita, Olga Mizenina, Diana Dudziak, Michel C. Nussenzweig, and Ralph M. Steinman. "A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12–independent but CD70-dependent mechanism in vivo." Journal of Experimental Medicine 204, no. 5 (April 16, 2007): 1095–106. http://dx.doi.org/10.1084/jem.20070176.
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Interferon (IFN)-γ, a cytokine critical for resistance to infection and tumors, is produced by CD4+ helper T lymphocytes after stimulation by cultured dendritic cells (DCs) that secrete a cofactor, interleukin (IL)-12. We have identified a major IL-12–independent pathway whereby DCs induce IFN-γ–secreting T helper (Th)1 CD4+ T cells in vivo. This pathway requires the membrane-associated tumor necrosis family member CD70 and was identified by targeting the LACK antigen from Leishmania major within an antibody to CD205 (DEC-205), an uptake receptor on a subset of DCs. Another major DC subset, targeted with 33D1 anti-DCIR2 antibody, also induced IFN-γ in vivo but required IL-12, not CD70. Isolated CD205+ DCs expressed cell surface CD70 when presenting antigen to T cell receptor transgenic T cells, and this distinction was independent of maturation stimuli. CD70 was also essential for CD205+ DC function in vivo. Detection of the IL-12–independent IFN-γ pathway was obscured with nontargeted LACK, which was presented by both DC subsets. This in situ analysis points to CD70 as a decision maker for Th1 differentiation by CD205+ DCs, even in Th2-prone BALB/c animals and potentially in vaccine design. The results indicate that two DC subsets have innate propensities to differentially affect the Th1/Th2 balance in vivo and by distinct mechanisms.
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Sanders, Rogier W., Esther C. de Jong, Christopher E. Baldwin, Joost H. N. Schuitemaker, Martien L. Kapsenberg, and Ben Berkhout. "Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells." Journal of Virology 76, no. 15 (August 1, 2002): 7812–21. http://dx.doi.org/10.1128/jvi.76.15.7812-7821.2002.
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ABSTRACT Dendritic cells (DC) support human immunodeficiency virus type 1 (HIV-1) transmission by capture of the virus particle in the mucosa and subsequent transport to the draining lymph node, where HIV-1 is presented to CD4+ Th cells. Virus transmission involves a high-affinity interaction between the DC-specific surface molecule DC-SIGN and the viral envelope glycoprotein gp120 and subsequent internalization of the virus, which remains infectious. The mechanism of viral transmission from DC to T cells is currently unknown. Sentinel immature DC (iDC) develop into Th1-promoting effector DC1 or Th2-promoting DC2, depending on the activation signals. We studied the ability of these effector DC subsets to support HIV-1 transmission in vitro. Compared with iDC, virus transmission is greatly upregulated for the DC1 subset, whereas DC2 cells are inactive. Increased transmission by DC1 correlates with increased expression of ICAM-1, and blocking studies confirm that ICAM-1 expression on DC is important for HIV transmission. The ICAM-1-LFA-1 interaction is known to be important for immunological cross talk between DC and T cells, and our results indicate that this cell-cell contact is exploited by HIV-1 for efficient transmission.
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Nijmeijer, Bernadien M., Catharina J. M. Langedijk, and Teunis B. H. Geijtenbeek. "Mucosal Dendritic Cell Subsets Control HIV-1’s Viral Fitness." Annual Review of Virology 7, no. 1 (September 29, 2020): 385–402. http://dx.doi.org/10.1146/annurev-virology-020520-025625.
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Dendritic cell (DC) subsets are abundantly present in genital and intestinal mucosal tissue and are among the first innate immune cells that encounter human immunodeficiency virus type 1 (HIV-1) after sexual contact. Although DCs have specific characteristics that greatly enhance HIV-1 transmission, it is becoming evident that most DC subsets also have virus restriction mechanisms that exert selective pressure on the viruses during sexual transmission. In this review we discuss the current concepts of the immediate events following viral exposure at genital mucosal sites that lead to selection of specific HIV-1 variants called transmitted founder (TF) viruses. We highlight the importance of the TF HIV-1 phenotype and the role of different DC subsets in establishing infection. Understanding the biology of HIV-1 transmission will contribute to the design of novel treatment strategies preventing HIV-1 dissemination.
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Said, André, and Günther Weindl. "Regulation of Dendritic Cell Function in Inflammation." Journal of Immunology Research 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/743169.
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Dendritic cells (DC) are professional antigen presenting cells and link the innate and adaptive immune system. During steady state immune surveillance in skin, DC act as sentinels against commensals and invading pathogens. Under pathological skin conditions, inflammatory cytokines, secreted by surrounding keratinocytes, dermal fibroblasts, and immune cells, influence the activation and maturation of different DC populations including Langerhans cells (LC) and dermal DC. In this review we address critical differences in human DC subtypes during inflammatory settings compared to steady state. We also highlight the functional characteristics of human DC subsets in inflammatory skin environments and skin diseases including psoriasis and atopic dermatitis. Understanding the complex immunoregulatory role of distinct DC subsets in inflamed human skin will be a key element in developing novel strategies in anti-inflammatory therapy.
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Jongbloed, Sarah L., Andrew J. Kassianos, Kylie J. McDonald, Georgina J. Clark, Xinsheng Ju, Catherine E. Angel, Chun-Jen J. Chen, et al. "Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens." Journal of Experimental Medicine 207, no. 6 (May 17, 2010): 1247–60. http://dx.doi.org/10.1084/jem.20092140.
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The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141+ DC subset. CD141+ DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-β, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c+ DC subset. Polyinosine-polycytidylic acid (poly I:C)–activated CD141+ DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8+ cytotoxic T lymphocytes than poly I:C–activated CD1c+ DCs. Importantly, CD141+ DCs, but not CD1c+ DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141+ DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8α+ DC subset. The data demonstrate a role for CD141+ DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.
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Huch, Jennifer H., Anthony L. Cunningham, Ann M. Arvin, Najla Nasr, Saskia J. A. M. Santegoets, Eric Slobedman, Barry Slobedman, and Allison Abendroth. "Impact of Varicella-Zoster Virus on Dendritic Cell Subsets in Human Skin during Natural Infection." Journal of Virology 84, no. 8 (February 3, 2010): 4060–72. http://dx.doi.org/10.1128/jvi.01450-09.
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ABSTRACT Varicella-zoster virus (VZV) causes varicella and herpes zoster, diseases characterized by distinct cutaneous rashes. Dendritic cells (DC) are essential for inducing antiviral immune responses; however, the contribution of DC subsets to immune control during natural cutaneous VZV infection has not been investigated. Immunostaining showed that compared to normal skin, the proportion of cells expressing DC-SIGN (a dermal DC marker) or DC-LAMP and CD83 (mature DC markers) were not significantly altered in infected skin. In contrast, the frequency of Langerhans cells was significantly decreased in VZV-infected skin, whereas there was an influx of plasmacytoid DC, a potent secretor of type I interferon (IFN). Langerhans cells and plasmacytoid DC in infected skin were closely associated with VZV antigen-positive cells, and some Langerhans cells and plasmacytoid DC were VZV antigen positive. To extend these in vivo observations, both plasmacytoid DC (PDC) isolated from human blood and Langerhans cells derived from MUTZ-3 cells were shown to be permissive to VZV infection. In VZV-infected PDC cultures, significant induction of alpha IFN (IFN-α) did not occur, indicating the VZV inhibits the capacity of PDC to induce expression of this host defense cytokine. This study defines changes in the response of DC which occur during cutaneous VZV infection and implicates infection of DC subtypes in VZV pathogenesis.
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Coquerelle, Caroline, and Muriel Moser. "DC subsets in positive and negative regulation of immunity." Immunological Reviews 234, no. 1 (March 2010): 317–34. http://dx.doi.org/10.1111/j.0105-2896.2009.00887.x.
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Geissmann, Frederic. "The real thing: How to make human DC subsets." Journal of Experimental Medicine 212, no. 3 (March 9, 2015): 285. http://dx.doi.org/10.1084/jem.2123insight2.
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Hubert, Gobbini, Bendriss-Vermare, Caux, and Valladeau-Guilemond. "Human Tumor-Infiltrating Dendritic Cells: From in Situ Visualization to High-Dimensional Analyses." Cancers 11, no. 8 (July 30, 2019): 1082. http://dx.doi.org/10.3390/cancers11081082.
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The interaction between tumor cells and the immune system is considered to be a dynamic process. Dendritic cells (DCs) play a pivotal role in anti-tumor immunity owing to their outstanding T cell activation ability. Their functions and activities are broad ranged, triggering different mechanisms and responses to the DC subset. Several studies identified in situ human tumor-infiltrating DCs by immunostaining using a limited number of markers. However, considering the heterogeneity of DC subsets, the identification of each subtype present in the immune infiltrate is essential. To achieve this, studies initially relied on flow cytometry analyses to provide a precise characterization of tumor-associated DC subsets based on a combination of multiple markers. The concomitant development of advanced technologies, such as mass cytometry or complete transcriptome sequencing of a cell population or at a single cell level, has provided further details on previously identified populations, has unveiled previously unknown populations, and has finally led to the standardization of the DCs classification across tissues and species. Here, we review the evolution of tumor-associated DC description, from in situ visualization to their characterization with high-dimensional technologies, and the clinical use of these findings specifically focusing on the prognostic impact of DCs in cancers.
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Ito, Tomoki, Holger Kanzler, Omar Duramad, Wei Cao, and Yong-Jun Liu. "Specialization, kinetics, and repertoire of type 1 interferon responses by human plasmacytoid predendritic cells." Blood 107, no. 6 (March 15, 2006): 2423–31. http://dx.doi.org/10.1182/blood-2005-07-2709.
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AbstractRecent studies suggest plasmacytoid predendritic cells (pDCs) and myeloid dendritic cells (mDCs) have the functional plasticity to produce similar amounts of type 1 interferons (IFNs) and interleukin-12 (IL-12), challenging the concept and existence of DC subsets with distinct function. In this study, we demonstrate that previous studies showed human pDCs produce large amounts of IL-12 because of contaminating mDCs. Using highly purified human DC subsets, we found that although pDCs make 300 times more IFN-α than mDCs and mDCs make 13 times more IL-12 p70 than pDCs in response to all the toll-like receptor ligands and CD40 ligands, pDCs rapidly make large amounts of IFN-α within the first 12 hours of activation and become refractory to further stimulation. pDCs preferentially expressed the transcriptional factors critical for type 1 IFN, but not for IL-12 transcription, and they dedicated 60% of new transcriptional activity to make 19 type 1 IFN subtypes. This study provides formal proof that the plasticity of DC subsets is limited and that different DC subsets evolve to perform distinct functions in linking innate and adaptive immunity. (Blood. 2006;107:2423-2431)
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Lissoni, P., F. Brivio, R. Ferrante, L. Vigore, M. Vaghi, E. Fumagalli, R. Bucovec, F. Malugani, and L. Fumagalli. "Circulating Immature and Mature Dendritic Cells in Relation to Lymphocyte Subsets in Patients with Gastrointestinal Tract Cancer." International Journal of Biological Markers 15, no. 1 (January 2000): 22–25. http://dx.doi.org/10.1177/172460080001500104.
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Cancer-related deficiency in circulating dendritic cells (DC), whose important anticancer role is well established, has been proven to be associated with lymphocytopenia. This study was performed to evaluate which lymphocyte subset is most markedly related to the failure of the DC system. The study included 30 patients with gastrointestinal tract cancer, 10 of whom had distant organ metastases. Immature and mature DCs were measured by FACS and monoclonal antibodies against CD123 and CD11c antigens, respectively. Low levels of immature and mature DCs were observed in 63% and 43% of patients, respectively. Patients with low levels of circulating mature DCs had significantly lower values of T lymphocytes, T helper lymphocytes and NK cells than those with normal mature DC levels. In contrast, no significant difference was seen between patients with normal or abnormally low values of immature DCs. Conversely, patients with a decreased number of T lymphocytes, T helper lymphocytes and NK cells showed significantly lower values of circulating mature DCs than those with lymphocyte subsets within the normal range, whereas no difference was seen in immature DC amounts. This study suggests that only mature DC deficiency may be associated with important lymphocyte subset alterations in cancer patients, whereas deficiency in immature DCs does not seem to be related to other immune cell disorders.
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Duong, Ellen, Timothy Fessenden, Arjun Bhutkar, and Stefani Spranger. "538 Harnessing cross-dressing dendritic cells to strengthen anti-tumor immunity." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A574. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0538.
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BackgroundCytotoxic (CD8+) T-cells are required for tumor eradication and durable anti-tumor immunity.1 The induction of tumor-reactive CD8+ T-cells is predominately attributed to a subset of dendritic cells (DC) called Batf3-driven DC1, given their robust ability to cross-present antigens for T-cell priming and their role in effector T-cell recruitment.2–4 Presence of the DC1 signature in tumors correlates with improved survival and response to immunotherapies.5–7 Yet, most tumors with a DC1 infiltrate still progress, suggesting that while DC1 can initiate tumor-reactive CD8+ T-cell responses, they are unable to sustain them. Therefore, there is a critical need to identify and engage additional stimulatory DC subsets to strengthen anti-tumor immunity and boost immunotherapy responses.MethodsTo identify DC subsets that drive poly-functional CD8+ T-cell responses, we compared the DC infiltrate of a spontaneously regressing tumor with a progressing tumor. Multicolor flow immunophenotyping and single-cell RNA-sequencing were used to profile the DC compartment of both tumors. IFNγ-ELISpot was performed on splenocytes to assess for systemic tumor-reactive T-cell responses. Sorted DC subsets from tumors were co-cultured with TCR-transgenic T-cells ex vivo to evaluate their stimulatory capacity. Cross-dressing (in vivo/ex vivo) was assayed by staining for transfer of tumor-derived H-2b MHC complexes to Balb/c DC, which express the H-2d haplotype. Protective systemic immunity was assayed via contralateral flank tumor outgrowth experiments.ResultsRegressor tumors were infiltrated with more cross-presenting DC1 than progressor tumors. However, tumor-reactive CD8+ T-cell responses and tumor control were preserved in Batf3-/- mice lacking DC1, indicating that anti-tumor immune responses could be induced independent of DC1. Through functional assays, we established that anti-tumor immunity against regressor tumors required CD11c+ DC and cGAS/STING-independent type-I-interferon-sensing. Single-cell RNA-sequencing of the immune infiltrate of regressor tumors revealed a novel CD11b+ DC subset expressing an interferon-stimulated gene signature (ISG+ DC). Flow studies demonstrated that ISG+ DC were more enriched in regressor tumors than progressor tumors. We showed that ISG+ DC could activate CD8+ T-cells by cross-dressing with tumor-derived peptide-MHC complexes, thereby bypassing the requirement for cross-presentation to initiate CD8+ T-cell-driven immunity. ISG+ DC highly expressed cytosolic dsRNA sensors (RIG-I/MDA5) and could be therapeutically harnessed by exogenous addition of a dsRNA analog to drive protective CD8+ T-cell responses in DC1-deficient mice.ConclusionsThe DC infiltrate in tumors can dictate the strength of anti-tumor immunity. Harnessing multiple stimulatory DC subsets, such as cross-presenting DC1 and cross-dressing ISG+ DC, provides a therapeutic opportunity to enhance anti-tumor immunity and increase immunotherapy responses.ReferencesFridman WH, et al. The immune contexture in human tumours: impact on clinical outcome. Nature Reviews Cancer 2012;12(4): p. 298–306.Hildner K, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 2008;322(5904):p. 1097–100.Spranger S, et al. Tumor-Residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 2017;31(5):p. 711–723.e4.Roberts, EW, et al., Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 2016;30(2): p. 324–336.Broz ML, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 2014;26(5): p. 638–52.Salmon H., et al., Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity, 2016. 44(4): p. 924–38.Sánchez-Paulete AR, et al., Cancer immunotherapy with immunomodulatory anti-CD137 and Anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov, 2016;6(1):p. 71–9.
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Kreutz, Martin, Paul J. Tacken, and Carl G. Figdor. "Targeting dendritic cells—why bother?" Blood 121, no. 15 (April 11, 2013): 2836–44. http://dx.doi.org/10.1182/blood-2012-09-452078.
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Abstract Vaccination is among the most efficient forms of immunotherapy. Although sometimes inducing lifelong protective B-cell responses, T-cell–mediated immunity remains challenging. Targeting antigen to dendritic cells (DCs) is an extensively explored concept aimed at improving cellular immunity. The identification of various DC subsets with distinct functional characteristics now allows for the fine-tuning of targeting strategies. Although some of these DC subsets are regarded as superior for (cross-) priming of naive T cells, controversies still remain about which subset represents the best target for immunotherapy. Because targeting the antigen alone may not be sufficient to obtain effective T-cell responses, delivery systems have been developed to target multiple vaccine components to DCs. In this Perspective, we discuss the pros and cons of targeting DCs: if targeting is beneficial at all and which vaccine vehicles and immunization routes represent promising strategies to reach and activate DCs.
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van de Ven, Rieneke, Mari F. C. M. van den Hout, Jelle J. Lindenberg, Berbel J. R. Sluijter, Paul A. M. van Leeuwen, Sinéad M. Lougheed, Sybren Meijer, M. Petrousjka van den Tol, Rik J. Scheper, and Tanja D. de Gruijl. "Characterization of four conventional dendritic cell subsets in human skin-draining lymph nodes in relation to T-cell activation." Blood 118, no. 9 (September 1, 2011): 2502–10. http://dx.doi.org/10.1182/blood-2011-03-344838.
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Abstract To increase (tumor) vaccine efficacy, there is an urgent need for phenotypic and functional characterization of human dendritic cell (DC) subsets residing in lymphoid tissues. In this study we identified and functionally tested 4 human conventional DC (cDC) subsets within skin-draining sentinel lymph nodes (SLNs) from early-stage melanoma patients. These SLNs were all tumor negative and were removed on average 44 days after excision of the primary melanoma. As such, they were considered representative of steady-state conditions. On comparison with skin-migrated cDC, 2 CD1a+ subsets were identified as most likely skin-derived CD11cint Langerhans cells (LC) with intracellular langerin and E-cadherin expression or as CD11chi dermal DCs with variable expression of langerin. Two other CD1a− LN-residing cDC subsets were characterized as CD14−BDCA3hiCD103− and CD14+BDCA3loCD103+, respectively. Whereas the CD1a+ skin-derived subsets displayed greater levels of phenotypic maturation, they were associated with lower levels of inflammatory cytokine release and were inferior in terms of allogeneic T-cell priming and IFNγ induction. Thus, despite their higher maturation state, skin-derived cDCs (and LCs in particular) proved inferior T-cell activators compared with the CD1a− cDC subsets residing in melanoma-draining LNs. These observations should be considered in the design of DC-targeting immunotherapies.
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Mohty, Mohamad, David Jarrossay, Marina Lafage-Pochitaloff, Christine Zandotti, Francine Brière, Xavier-Nicolas de Lamballeri, Daniel Isnardon, Danielle Sainty, Daniel Olive, and Béatrice Gaugler. "Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment." Blood 98, no. 13 (December 15, 2001): 3750–56. http://dx.doi.org/10.1182/blood.v98.13.3750.
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Abstract Dendritic cells (DCs) are responsible for the initiation of immune responses. Two distinct subsets of blood DCs have been characterized thus far. Myeloid DCs (MDCs) and plasmacytoid monocytes (PDCs) were shown to be able to promote polarization of naive T cells. This study shows a dramatic quantitative imbalance in both circulating blood DC subsets in 37 patients with acute myeloid leukemias. Eleven patients (30%) displayed a normal quantitative profile (MDC mean, 0.37% ± 0.21%; range, 0.01% to 0.78%; PDC mean, 0.21% ± 0.24%; range, 0.04% to 0.62%), whereas 22 (59%) showed a tremendous expansion of MDCs (9 patients: mean, 16.76% ± 14.03%; range, 1.36% to 41%), PDCs (4 patients: mean, 7.28% ± 6.84%; range, 1% to 14%), or both subsets (9 patients: MDC mean, 10.86% ± 12.36%; range, 1.02% to 37.1%; PDC mean, 4.25% ± 3.78%; range, 1.14% to 13.04%). Finally, in 4 patients (11%), no DC subsets were detectable. Both MDC and PDC subsets exhibited the original leukemic chromosomal abnormality. Ex vivo, leukemic PDCs, but not leukemic MDCs, had impaired capacity for maturation and decreased allostimulatory activity. Also, leukemic PDCs were altered in their ability to secrete interferon-α. These data provide evidence that DC subsets in vivo may be affected by leukemogenesis and may contribute to leukemia escape from immune control.
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van de Laar, Lianne, Paul J. Coffer, and Andrea M. Woltman. "Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy." Blood 119, no. 15 (April 12, 2012): 3383–93. http://dx.doi.org/10.1182/blood-2011-11-370130.
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Dendritic cells (DCs) represent a small and heterogeneous fraction of the hematopoietic system, specialized in antigen capture, processing, and presentation. The different DC subsets act as sentinels throughout the body and perform a key role in the induction of immunogenic as well as tolerogenic immune responses. Because of their limited lifespan, continuous replenishment of DC is required. Whereas the importance of GM-CSF in regulating DC homeostasis has long been underestimated, this cytokine is currently considered a critical factor for DC development under both steady-state and inflammatory conditions. Regulation of cellular actions by GM-CSF depends on the activation of intracellular signaling modules, including JAK/STAT, MAPK, PI3K, and canonical NF-κB. By directing the activity of transcription factors and other cellular effector proteins, these pathways influence differentiation, survival and/or proliferation of uncommitted hematopoietic progenitors, and DC subset–specific precursors, thereby contributing to specific aspects of DC subset development. The specific intracellular events resulting from GM-CSF–induced signaling provide a molecular explanation for GM-CSF–dependent subset distribution as well as clues to the specific characteristics and functions of GM-CSF–differentiated DCs compared with DCs generated by fms-related tyrosine kinase 3 ligand. This knowledge can be used to identify therapeutic targets to improve GM-CSF–dependent DC-based strategies to regulate immunity.
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Vallop Josiassen, Michael, and Kajsa Paulsson. "Dendritic cell dysfunction and implications for dendritic cell-based therapy in colorectal cancer." Drugs and Therapy Studies 1, no. 1 (November 2, 2011): 14. http://dx.doi.org/10.4081/dts.2011.e14.
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Clinical trials and experimental models indicate that dendritic-cell-based immunotherapy is promising for treatment of different types of cancer. However, dendritic cells (DCs) have strong immune-regulatory capacities and can not only stimulate but also dampen immune responses. It is also well known that the different DC subsets strongly influence the magnitude and quality of adaptive immune responses. In this review, to improve understanding of the DC-based immunotherapy approach, we briefly describe different DC subsets and the differentiation, maturation, and activation of these cells. One form of cancer for which there is a strong need to find, establish, and standardize new, alternative therapies is colorectal cancer. This review discusses some of the factors, including those involved in DC dysfunction, that we believe to be of major influence in DC therapy in colorectal cancer.
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Veron, Philippe, Valérie Allo, Christel Rivière, Jacky Bernard, Anne-Marie Douar, and Carole Masurier. "Major Subsets of Human Dendritic Cells Are Efficiently Transduced by Self-Complementary Adeno-Associated Virus Vectors 1 and 2." Journal of Virology 81, no. 10 (February 21, 2007): 5385–94. http://dx.doi.org/10.1128/jvi.02516-06.
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ABSTRACT Dendritic cells (DC) are antigen-presenting cells pivotal for inducing immunity or tolerance. Gene transfer into DC is an important strategy for developing immunotherapeutic approaches against infectious pathogens and cancers. One of the vectors previously described for the transduction of human monocytes or DC is the recombinant adeno-associated virus (rAAV), with a genome conventionally packaged as a single-stranded (ss) molecule. Nevertheless, its use is limited by the poor and variable transduction efficiency of DC. In this study, AAV type 1 (AAV1) and AAV2 vectors, which expressed the enhanced green fluorescent protein and were packaged as ss or self-complementary (sc) duplex strands, were used to transduce different DC subsets generated ex vivo and the immunophenotypes, states of differentiation, and functions of the subsets were carefully examined. We show here for the first time that a single exposure of monocytes (Mo) or CD34+ progenitors (CD34) to sc rAAV1 or sc rAAV2 leads to high transduction levels (5 to 59%) of differentiated Mo-DC, Mo-Langerhans cells (LC), CD34-LC, or CD34-plasmacytoid DC (pDC), with no impact on their phenotypes and functional maturation of these cells, compared to those of exposure to ss rAAV. Moreover, we show that all these DC subpopulations can also be efficiently transduced after commitment to their differentiation pathways. Furthermore, these DC subsets transduced with sc rAAV1 expressing a tumor antigen were potent activators of a CD8+-T-cell clone. Altogether, these results show the high potential of sc AAV1 and sc AAV2 vectors to transduce ex vivo conventional DC, LC, or pDC or to directly target them in vivo for the design of new DC-based immunotherapies.
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SOILLEUX, Elizabeth J. "DC-SIGN (dendritic cell-specific ICAM-grabbing non-integrin) and DC-SIGN-related (DC-SIGNR): friend or foe?" Clinical Science 104, no. 4 (March 21, 2003): 437–46. http://dx.doi.org/10.1042/cs1040437.
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C-type lectins are calcium-dependent carbohydrate-binding proteins with a wide range of biological functions, many of which are related to immunity. DC-SIGN (dendritic cell-specific ICAM-grabbing non-integrin, where ICAM is intercellular adhesion molecule) is a recently described mannose-specific C-type lectin expressed by dendritic cells. Dendritic cells are potent antigen-presenting cells capable of activating T-lymphocytes. DC-SIGN, which is expressed by dendritic cells, binds to ICAM-3 on T-lymphocytes, therefore playing an important role in the activation of T-lymphocytes. DC-SIGN can also bind HIV, and the virus may remain bound to DC-SIGN for protracted periods. DC-SIGN may deliver bound HIV to permissive cell types, mediating infection with high efficiency. A closely related C-type lectin, DC-SIGN-related molecule (DC-SIGNR) has also been described. DC-SIGNR is expressed by restricted subsets of endothelial cells, but has similar ICAM-3 and HIV-binding properties to DC-SIGN. This review describes the mapping of DC-SIGN and DC-SIGNR to chromosome 19p13.3 adjacent to the previously described C-type lectin, CD23 [the low-affinity receptor for immunoglobulin E (FcERII)]. The similar genomic organization of these three genes is discussed and consideration is given to the evolutionary duplications that may underlie this arrangement. Both DC-SIGN and DC-SIGNR possess a neck region, made up of multiple repeats, which supports the ligand-binding domain. Consideration is given to the biological reasons underlying the considerable polymorphism in the numbers of repeats in DC-SIGNR, but not DC-SIGN. The expression patterns of both DC-SIGN and DC-SIGNR are discussed in detail, with particular attention to the expression of both molecules in the placenta, which may have implications for the vertical transmission of HIV. Since dendritic cells may be important in determining the phenotype of many immune responses, via effects on T-lymphocytes, the differential expression of DC-SIGN by particular dendritic cell subsets may have important implications for the immunobiological functions of DC-SIGN. Similarly, the expression of DC-SIGNR by very restricted subsets of endothelial cells may give clues to the function of DC-SIGNR. Finally, the role of DC-SIGN in pathology, particularly in infective and neoplastic processes, is discussed, followed by speculation about likely future developments in this field.
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Gallego, Carmen, Mathias Vétillard, Joseph Calmette, Mélanie Roriz, Viviana Marin-Esteban, Maximilien Evrard, Marie-Laure Aknin, et al. "CXCR4 signaling controls dendritic cell location and activation at steady state and in inflammation." Blood 137, no. 20 (May 20, 2021): 2770–84. http://dx.doi.org/10.1182/blood.2020006675.
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Abstract Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked. We addressed this question using natural CXCR4 mutants resistant to CXCL12-induced desensitization and harboring a gain of function that cause the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS), a rare immunodeficiency associated with high susceptibility to the pathogenesis of human papillomavirus (HPV). We report a reduction in the number of circulating plasmacytoid DCs (pDCs) in WHIM patients, whereas that of conventional DCs is preserved. This pattern was reproduced in an original mouse model of WS, enabling us to show that the circulating pDC defect can be corrected upon CXCR4 blockade and that pDC differentiation and function are preserved, despite CXCR4 dysfunction. We further identified proper CXCR4 signaling as a critical checkpoint for Langerhans cell and DC migration from the skin to lymph nodes, with corollary alterations of their activation state and tissue inflammation in a model of HPV-induced dysplasia. Beyond providing new hypotheses to explain the susceptibility of WHIM patients to HPV pathogenesis, this study shows that proper CXCR4 signaling establishes a migration threshold that controls DC egress from CXCL12-containing environments and highlights the critical and subset-specific contribution of CXCR4 signal termination to DC biology.