@article{DoehlerSchneiderEckertetal.2017, author = {D{\"o}hler, Anja and Schneider, Theresa and Eckert, Ina and Ribechini, Eliana and Andreas, Nico and Riemann, Marc and Reizis, Boris and Weih, Falk and Lutz, Manfred B.}, title = {RelB\(^{+}\) Steady-State Migratory Dendritic Cells Control the Peripheral Pool of the Natural Foxp3\(^{+}\) Regulatory T Cells}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, number = {726}, doi = {10.3389/fimmu.2017.00726}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158121}, year = {2017}, abstract = {Thymus-derived natural Foxp3\(^{+}\) CD4\(^{+}\) regulatory T cells (nTregs) play a key role in maintaining immune tolerance and preventing autoimmune disease. Several studies indicate that dendritic cells (DCs) are critically involved in the maintenance and proliferation of nTregs. However, the mechanisms how DCs manage to keep the peripheral pool at constant levels remain poorly understood. Here, we describe that the NF-κB/Rel family transcription factor RelB controls the frequencies of steady-state migratory DCs (ssmDCs) in peripheral lymph nodes and their numbers control peripheral nTreg homeostasis. DC-specific RelB depletion was investigated in CD11c-Cre × RelB\(^{fl/fl}\) mice (RelB\(^{DCko}\)), which showed normal frequencies of resident DCs in lymph nodes and spleen while the subsets of CD103\(^{-}\) Langerin\(^{-}\) dermal DCs (dDCs) and Langerhans cells but not CD103\(^{+}\) Langerin\(^{+}\) dDC of the ssmDCs in skin-draining lymph nodes were increased. Enhanced frequencies and proliferation rates were also observed for nTregs and a small population of CD4\(^{+}\) CD44\(^{high}\) CD25\(^{low}\) memory-like T cells (Tml). Interestingly, only the Tml but not DCs showed an increase in IL-2-producing capacity in lymph nodes of RelB\(^{DCko}\) mice. Blocking of IL-2 in vivo reduced the frequency of nTregs but increased the Tml frequencies, followed by a recovery of nTregs. Taken together, by employing RelB\(^{DCko}\) mice with increased frequencies of ssmDCs our data indicate a critical role for specific ssmDC subsets for the peripheral nTreg and IL-2\(^{+}\) Tml frequencies during homeostasis.}, language = {en} } @article{SilvaVilchesPletinckxLohnertetal.2017, author = {Silva-Vilches, Cinthia and Pletinckx, Katrien and Lohnert, Miriam and Pavlovic, Vladimir and Ashour, Diyaaeldin and John, Vini and Vendelova, Emilia and Kneitz, Susanne and Zhou, Jie and Chen, Rena and Reinheckel, Thomas and Mueller, Thomas D. and Bodem, Jochen and Lutz, Manfred B.}, title = {Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {7}, doi = {10.1371/journal.pone.0178114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158244}, pages = {e0178114}, year = {2017}, abstract = {Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3\(^{+}\) induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CT\(^{hi}\), CT\(^{lo}\)) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CT\(^{hi}\) conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CT\(^{lo}\)- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3\(^{+}\) iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CT\(^{lo}\)- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3\(^{+}\) Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.}, language = {en} } @article{HellmannLotherWursteretal.2017, author = {Hellmann, Anna-Maria and Lother, Jasmin and Wurster, Sebastian and Lutz, Manfred B. and Schmitt, Anna Lena and Morton, Charles Oliver and Eyrich, Matthias and Czakai, Kristin and Einsele, Hermann and Loeffler, Juergen}, title = {Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, number = {1716}, doi = {10.3389/fimmu.2017.01716}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169926}, year = {2017}, abstract = {Aspergillus fumigatus is the main cause of invasive fungal infections occurring almost exclusively in immunocompromised patients. An improved understanding of the initial innate immune response is key to the development of better diagnostic tools and new treatment options. Mice are commonly used to study immune defense mechanisms during the infection of the mammalian host with A. fumigatus. However, little is known about functional differences between the human and murine immune response against this fungal pathogen. Thus, we performed a comparative functional analysis of human and murine dendritic cells (DCs), macrophages, and polymorphonuclear cells (PMNs) using standardized and reproducible working conditions, laboratory protocols, and readout assays. A. fumigatus did not provoke identical responses in murine and human immune cells but rather initiated relatively specific responses. While human DCs showed a significantly stronger upregulation of their maturation markers and major histocompatibility complex molecules and phagocytosed A. fumigatus more efficiently compared to their murine counterparts, murine PMNs and macrophages exhibited a significantly stronger release of reactive oxygen species after exposure to A. fumigatus. For all studied cell types, human and murine samples differed in their cytokine response to conidia or germ tubes of A. fumigatus. Furthermore, Dectin-1 showed inverse expression patterns on human and murine DCs after fungal stimulation. These specific differences should be carefully considered and highlight potential limitations in the transferability of murine host-pathogen interaction studies.}, language = {en} } @article{LutzStroblSchuleretal.2017, author = {Lutz, Manfred B. and Strobl, Herbert and Schuler, Gerold and Romani, Nikolaus}, title = {GM-CSF monocyte-derived cells and Langerhans cells as part of the dendritic cell family}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, number = {1388}, doi = {10.3389/fimmu.2017.01388}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158730}, year = {2017}, abstract = {Dendritic cells (DCs) and macrophages (Mph) share many characteristics as components of the innate immune system. The criteria to classify the multitude of subsets within the mononuclear phagocyte system are currently phenotype, ontogeny, transcription patterns, epigenetic adaptations, and function. More recently, ontogenetic, transcriptional, and proteomic research approaches uncovered major developmental differences between Flt3L-dependent conventional DCs as compared with Mphs and monocyte-derived DCs (MoDCs), the latter mainly generated in vitro from murine bone marrow-derived DCs (BM-DCs) or human CD14\(^{+}\) peripheral blood monocytes. Conversely, in vitro GM-CSF-dependent monocyte-derived Mphs largely resemble MoDCs whereas tissue-resident Mphs show a common embryonic origin from yolk sac and fetal liver with Langerhans cells (LCs). The novel ontogenetic findings opened discussions on the terminology of DCs versus Mphs. Here, we bring forward arguments to facilitate definitions of BM-DCs, MoDCs, and LCs. We propose a group model of terminology for all DC subsets that attempts to encompass both ontogeny and function.}, language = {en} }