Publications by authors named "Björn E Clausen"

98 Publications

Revisiting Current Concepts on the Tolerogenicity of Steady-State Dendritic Cell Subsets and Their Maturation Stages.

J Immunol 2021 Apr;206(8):1681-1689

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55122 Mainz, Germany.

The original concept stated that immature dendritic cells (DC) act tolerogenically whereas mature DC behave strictly immunogenically. Meanwhile, it is also accepted that phenotypically mature stages of all conventional DC subsets can promote tolerance as steady-state migratory DC by transporting self-antigens to lymph nodes to exert unique functions on regulatory T cells. We propose that in vivo 1) there is little evidence for a tolerogenic function of immature DC during steady state such as CD4 T cell anergy induction, 2) all tolerance as steady-state migratory DC undergo common as well as subset-specific molecular changes, and 3) these changes differ by quantitative and qualitative markers from immunogenic DC, which allows one to clearly distinguish tolerogenic from immunogenic migratory DC.
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http://dx.doi.org/10.4049/jimmunol.2001315DOI Listing
April 2021

Langerhans Cells Suppress CD8 T Cells In Situ during Mucocutaneous Acute Graft-Versus-Host Disease.

J Invest Dermatol 2020 Oct 19. Epub 2020 Oct 19.

Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address:

Acute graft-versus-host disease (aGVHD) induced by allogenic hematopoietic stem cell transplantation is an immunological disorder in which donor lymphocytes attack recipient organs. It has been proven that recipient nonhematopoietic tissue cells, such as keratinocytes, are sufficient as immunological targets for allogenic donor T cells, whereas Langerhans cells (LCs) are potent professional hematopoietic antigen-presenting cells existing in the target epidermis and eliminated during the early phase of mucocutaneous aGVHD. Moreover, LCs have been reported to negatively regulate various types of immune responses. Here, we present data showing that initial depletion of recipient LCs exacerbates mucocutaneous lesions in a murine model of allogenic bone marrow transplantation-induced aGVHD. Furthermore, another murine model of mucocutaneous aGVHD induced in mice with keratinocytes genetically expressing chicken ovalbumin by transfer of ovalbumin-specific CD8 OT-I cells also showed that LC-depleted recipient mice develop aggravated mucocutaneous disease owing to decreased apoptosis of skin-infiltrating OT-I cells. Moreover, coexisting LCs directly induce apoptosis and inhibit the proliferation of OT-I cells in vitro partially via B7 family proteins. Collectively, our results indicate that LCs negatively regulate mucocutaneous aGVHD-like lesions in situ by inhibiting the number of infiltrating CD8 T cells.
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http://dx.doi.org/10.1016/j.jid.2020.09.018DOI Listing
October 2020

Induction of Regulatory T Cells in Leishmania major‒Infected BALB/c Mice Does Not Require Langerin+ Dendritic Cells.

J Invest Dermatol 2021 Apr 14;141(4):936-938. Epub 2020 Sep 14.

Department of Dermatology, Faculty of Medicine, University of Cologne, Cologne, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.04.033DOI Listing
April 2021

Talin1 sets the stage for dendritic cell activation.

Authors:
Björn E Clausen

J Exp Med 2020 08;217(8)

Institute for Molecular Medicine and Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

In this issue of JEM, Lim et al. (https://doi.org/10.1084/jem.20191810) provide exciting new evidence that talin1 plays an essential role in dendritic cell (DC) maturation and activation. Using conditional knockout mice, they demonstrate that talin1 promotes the formation of a preassembled TLR-Myddosome signaling complex in steady-state DCs but not macrophages. This may explain why DCs respond faster and more vigorously to TLR ligand binding than their closely related macrophages.
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http://dx.doi.org/10.1084/jem.20200574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398172PMC
August 2020

Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis.

Immunity 2020 09 19;53(3):627-640.e5. Epub 2020 Jun 19.

Institut National de la Santé et de la Recherche Médicale (Inserm, UMR_S 1166), Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France. Electronic address:

Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C monocytes during NASH, underlying impaired KC self-renewal. Monocyte-derived KCs (MoKCs) gradually seeded the KC pool as disease progressed in a response to embryo-derived KC (EmKC) death. Those MoKCs were partly immature and exhibited a pro-inflammatory status compared to EmKCs. Yet, they engrafted the KC pool for the long term as they remained following disease regression while acquiring mature EmKC markers. While KCs as a whole favored hepatic triglyceride storage during NASH, EmKCs promoted it more efficiently than MoKCs, and the latter exacerbated liver damage, highlighting functional differences among KCs with different origins. Overall, our data reveal that KC homeostasis is impaired during NASH, altering the liver response to lipids, as well as KC ontogeny.
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http://dx.doi.org/10.1016/j.immuni.2020.06.003DOI Listing
September 2020

Selective AhR knockout in langerin-expressing cells abates Langerhans cells and polarizes Th2/Tr1 in epicutaneous protein sensitization.

Proc Natl Acad Sci U S A 2020 06 27;117(23):12980-12990. Epub 2020 May 27.

Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan;

The aryl hydrocarbon receptor (AhR) represents an environmental sensor regulating immune responses. In the skin, AhR is expressed in several cell types, including keratinocytes, epidermal Langerhans cells (LC), and dermal dendritic cells (DC). The mechanisms how AhR activates or inhibits cutaneous immune responses remain controversial, owing to differences in the cell-specific functions of AhR and the different activating ligands. Therefore, we sought to investigate the role of AhR in LC and langerin and negative DC in the skin. To this aim, we generated Langerin-specific and CD11c-specific knockout () mice lacking AhR, respectively, in LC and Langerin dermal DC and in all CD11c cells. These were then tested in an epicutaneous protein (ovalbumin, Ova) sensitization model. Immunofluorescence microscopy and flow cytometry revealed that Langerin-AhR but not CD11c-AhR mice harbored a decreased number of LC with fewer and stunted dendrites in the epidermis as well as a decreased number of LC in skin-draining lymph nodes (LN). Moreover, in the absence of AhR, we detected an enhanced T helper type-2 (Th2) [increased interleukin 5 (IL-5) and interleukin 13 (IL-13)] and T regulatory type-1 (Tr1) (IL-10) response when LN cells were challenged with Ova in vitro, though the number of regulatory T cells (Treg) in the LN remained comparable. Langerin-AhR mice also exhibited increased blood levels of Ova-specific immunoglobulin E (IgE). In conclusion, deletion of AhR in langerin-expressing cells diminishes the number and activation of LC, while enhancing Th2 and Tr1 responses upon epicutaneous protein sensitization.
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http://dx.doi.org/10.1073/pnas.1917479117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293700PMC
June 2020

Tnfaip3 expression in pulmonary conventional type 1 Langerin-expressing dendritic cells regulates T helper 2-mediated airway inflammation in mice.

Allergy 2020 10 14;75(10):2587-2598. Epub 2020 Jun 14.

Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.

Background: Conventional type 1 dendritic cells (cDC1s) control anti-viral and anti-tumor immunity by inducing antigen-specific cytotoxic CD8 T-cell responses. Controversy exists whether cDC1s also control CD4 T helper 2 (Th2) cell responses, since suppressive and activating roles have been reported. DC activation status, controlled by the transcription factor NF-κB, might determine the precise outcome of Th-cell differentiation upon encounter with cDC1s. To investigate the role of activated cDC1s in Th2-driven immune responses, pulmonary cDC1s were activated by targeted deletion of A20/Tnfaip3, a negative regulator of NF-κB signaling.

Methods: To target pulmonary cDC1s, Cd207 (Langerin)-mediated excision of A20/Tnfaip3 was used, generating Tnfaip3 xCd207 (Tnfaip3 ) mice. Mice were exposed to house dust mite (HDM) to provoke Th2-mediated immune responses.

Results: Mice harboring Tnfaip3-deficient cDC1s did not develop Th2-driven eosinophilic airway inflammation upon HDM exposure, but rather showed elevated numbers of IFNγ-expressing CD8 T cells. In addition, Tnfaip3 mice harbored increased numbers of IL-12-expressing cDC1s and elevated PD-L1 expression in all pulmonary DC subsets. Blocking either IL-12 or IFNγ in Tnfaip3 mice restored Th2 responses, whereas administration of recombinant IFNγ during HDM sensitization in C57Bl/6 mice blocked Th2 development.

Conclusions: These findings indicate that the activation status of cDC1s, shown by their specific expression of co-inhibitory molecules and cytokines, critically contributes to the development of Th2 cell-mediated disorders, most likely by influencing IFNγ production in CD8 T cells.
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http://dx.doi.org/10.1111/all.14334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687104PMC
October 2020

Meeting Report of the 16th International Langerhans Cell Workshop: Recent Developments in Langerhans Cell and Skin Dendritic Cell Biology and their Therapeutic Application.

J Invest Dermatol 2020 07 19;140(7):1315-1319. Epub 2020 Mar 19.

Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1016/j.jid.2020.02.022DOI Listing
July 2020

E-Cadherin is Dispensable to Maintain Langerhans Cells in the Epidermis.

J Invest Dermatol 2020 01 28;140(1):132-142.e3. Epub 2019 Jun 28.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. Electronic address:

The cell adhesion molecule E-cadherin is a major component of adherens junctions and marks Langerhans cells (LC), the only dendritic cell (DC) population of the epidermis. LC form a dense network and attach themselves to the surrounding keratinocytes via homophilic E-cadherin binding. LC activation, mobilization, and migration require a reduction in LC E-cadherin expression. To determine whether E-cadherin plays a role in regulating LC homeostasis and function, we generated CD11c-specific E-cadherin knockout mice (CD11c-Ecad). In the absence of E-cadherin-mediated cell adhesion, LC numbers remained stable and similar as in control mice, even in aged animals. Intriguingly, E-cadherin-deficient LC displayed a dramatically changed morphology characterized by a more rounded cell body and fewer dendrites than wild-type cells. Nevertheless, maturation and migration of LC lacking E-cadherin was not altered, neither under steady-state nor inflammatory conditions. Accordingly, CD11c-Ecad and control mice developed comparable contact hypersensitivity reactions and imiquimod-triggered psoriatic skin inflammation, indicating that E-cadherin on LC does not influence their ability to orchestrate T cell-mediated immunity. In conclusion, our data demonstrate that E-cadherin is dispensable to maintain LC in the epidermis and does not regulate LC maturation, migration, and function.
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http://dx.doi.org/10.1016/j.jid.2019.06.132DOI Listing
January 2020

LangerinCD8 Dendritic Cells in the Splenic Marginal Zone: Not So Marginal After All.

Front Immunol 2019 12;10:741. Epub 2019 Apr 12.

Paul Klein Center for Immune Intervention, Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Dendritic cells (DC) fulfill an essential sentinel function within the immune system, acting at the interface of innate and adaptive immunity. The DC family, both in mouse and man, shows high functional heterogeneity in order to orchestrate immune responses toward the immense variety of pathogens and other immunological threats. In this review, we focus on the LangerinCD8 DC subpopulation in the spleen. LangerinCD8 DC exhibit a high ability to take up apoptotic/dying cells, and therefore they are essential to prime and shape CD8 T cell responses. Next to the induction of immunity toward blood-borne pathogens, i.e., viruses, these DC are important for the regulation of tolerance toward cell-associated self-antigens. The ontogeny and differentiation pathways of CD8CD103 DC should be further explored to better understand the immunological role of these cells as a prerequisite of their therapeutic application.
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http://dx.doi.org/10.3389/fimmu.2019.00741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474365PMC
August 2020

TLR7 Controls VSV Replication in CD169 SCS Macrophages and Associated Viral Neuroinvasion.

Front Immunol 2019 15;10:466. Epub 2019 Mar 15.

Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.

Vesicular stomatitis virus (VSV) is an insect-transmitted rhabdovirus that is neurovirulent in mice. Upon peripheral VSV infection, CD169 subcapsular sinus (SCS) macrophages capture VSV in the lymph, support viral replication, and prevent CNS neuroinvasion. To date, the precise mechanisms controlling VSV infection in SCS macrophages remain incompletely understood. Here, we show that Toll-like receptor-7 (TLR7), the main sensing receptor for VSV, is central in controlling lymph-borne VSV infection. Following VSV skin infection, TLR7 mice display significantly less VSV titers in the draining lymph nodes (dLN) and viral replication is attenuated in SCS macrophages. In contrast to effects of TLR7 in impeding VSV replication in the dLN, TLR7 mice present elevated viral load in the brain and spinal cord highlighting their susceptibility to VSV neuroinvasion. By generating novel TLR7 floxed mice, we interrogate the impact of cell-specific TLR7 function in anti-viral immunity after VSV skin infection. Our data suggests that TLR7 signaling in SCS macrophages supports VSV replication in these cells, increasing LN infection and may account for the delayed onset of VSV-induced neurovirulence observed in TLR7 mice. Overall, we identify TLR7 as a novel and essential host factor that critically controls anti-viral immunity to VSV. Furthermore, the novel mouse model generated in our study will be of valuable importance to shed light on cell-intrinsic TLR7 biology in future studies.
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http://dx.doi.org/10.3389/fimmu.2019.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428728PMC
September 2020

Production of Extracellular Adenosine by CD73 Dendritic Cells Is Crucial for Induction of Tolerance in Contact Hypersensitivity Reactions.

J Invest Dermatol 2019 03 28;139(3):541-551. Epub 2018 Oct 28.

Department of Dermatology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany. Electronic address:

Dendritic cells (DCs) express the ecto-5'-nucleotidase CD73 that generates immunosuppressive adenosine (Ado) by dephosphorylation of extracellular Ado monophosphate and diphosphate. To investigate whether CD73-derived Ado has immune-suppressive activity, 2,4-dinitrothiocyanobenzene (DNTB) was applied to skin of wild-type (WT) or CD73-deficient (CD73) mice, followed by sensitization and challenge with 2,4-dinitrofluorobenzene. In this model, we show the induction of tolerance by DNTB against 2,4-dinitrofluorobenzene only in WT but not in CD73 mice. Analysis of skin DCs showed increased expression of CD73 after application of DNTB in WT mice. That was accompanied by elevated concentrations of extracellular Ado in the lymph node. Moreover, T cells expressed markers for anergy, namely EGR2 and NDRG1 in DNTB-treated WT mice and they exhibited impaired proliferation upon ex vivo re-stimulation. Similarly, in vitro we observed that Ado-producing WT DCs, but not CD73 DCs, rendered transgenic T cells from OTII mice (OTII T cells) hyporeactive, decreased their T-cell costimulatory signaling, and induced up-regulation of EGR2 and NDRG1. Thus, these data show that expression of CD73 by DCs, which triggers elevated levels of extracellular Ado, is a crucial mechanism for the induction of anergic T cells and tolerance.
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http://dx.doi.org/10.1016/j.jid.2018.10.016DOI Listing
March 2019

Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis.

J Invest Dermatol 2019 03 24;139(3):638-647. Epub 2018 Oct 24.

Center of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Center of Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center of Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung, DZHK), Rhine-Main, Germany. Electronic address:

Besides skin inflammation, patients with severe psoriasis suffer from an increased risk of cardiovascular mortality. IL-17A plays a central role in the development of psoriasis and might connect skin and vascular disease. The aim of this study was to clarify whether anti-IL-17A therapy could also ameliorate the vascular dysfunction associated with severe psoriasis. We analyzed three murine models with varying severities of psoriasis-like skin disease concerning their vascular function and inflammation: (i) K14-IL-17A mice with keratinocyte-specific IL-17A overexpression and an early-onset severe psoriasis-like phenotype; (ii) homozygous CD11c-IL-17A and heterozygous CD11c-IL-17A mice overexpressing IL-17A in CD11c cells, leading to a delayed onset of moderate psoriasis-like skin disease; and (iii) the acute model of imiquimod-induced psoriasis-like skin inflammation. Similar to the severity of skin disease, vascular dysfunction correlated with peripheral IL-17A levels and neutrophil infiltration into the aortic vessel wall. Successful anti-IL-17A treatment of psoriatic skin lesions diminished peripheral oxidative stress levels, proinflammatory cytokines, and vascular inflammation. These data highlight the pivotal role of IL-17A linking the development of skin lesions and vascular disease in psoriasis. Anti-IL-17A therapy might thus represent a useful approach to attenuate and prevent vascular disease in psoriasis patients.
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http://dx.doi.org/10.1016/j.jid.2018.09.021DOI Listing
March 2019

Dermal CD207-Negative Migratory Dendritic Cells Are Fully Competent to Prime Protective, Skin Homing Cytotoxic T-Lymphocyte Responses.

J Invest Dermatol 2019 02 6;139(2):422-429. Epub 2018 Oct 6.

Institute for Immunology, University Medical Center Mainz, Germany; Research Centre for Immunotherapy, University Medical Center Mainz, Mainz, Germany. Electronic address:

Dendritic cells (DCs) are important inducers and regulators of T-cell responses. They are able to activate and modulate the differentiation of CD4 and CD8 T cells. In the skin, there are at least five phenotypically distinct DC subpopulations that can be distinguished by differential expression of the cell surface markers CD207, CD103, and CD11b. Previous studies have suggested that dermal CD11bCD207 conventional type 1 DCs are indispensable for the priming of a skin homing cytotoxic T-lymphocyte response. However, conventional type 1 DCs are also the only skin DC subset capable of cross-presenting exogenous antigens on major histocompatibility complex class I. Thus, it remained unclear whether for antigens that do not require cross-presentation, such as viruses that infect DCs, other DC subtypes in the skin can contribute to cytotoxic T-lymphocyte priming. To address this question, we used a transgenic mouse model that allows inducible expression and presentation of a model antigen on selected subsets of dermal DCs. We show that for antigens presented via the conventional major histocompatibility complex class I presentation pathway, CD207 dermal DCs are fully competent to prime a skin homing cytotoxic T-lymphocyte response that is capable of protection against a local virus challenge and gives rise to skin resident memory CD8 T cells.
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http://dx.doi.org/10.1016/j.jid.2018.08.022DOI Listing
February 2019

Langerin+ DCs regulate innate IL-17 production in the oral mucosa during Candida albicans-mediated infection.

PLoS Pathog 2018 05 21;14(5):e1007069. Epub 2018 May 21.

Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.

The opportunistic fungal pathogen Candida albicans frequently causes diseases such as oropharyngeal candidiasis (OPC) in immunocompromised individuals. Although it is well appreciated that the cytokine IL-17 is crucial for protective immunity against OPC, the cellular source and the regulation of this cytokine during infection are still a matter of debate. Here, we directly visualized IL-17 production in the tongue of experimentally infected mice, thereby demonstrating that this key cytokine is expressed by three complementary subsets of CD90+ leukocytes: RAG-dependent αβ and γδ T cells, as well as RAG-independent ILCs. To determine the regulation of IL-17 production at the onset of OPC, we investigated in detail the myeloid compartment of the tongue and found a heterogeneous and dynamic mononuclear phagocyte (MNP) network in the infected tongue that consists of Zbtb46-Langerin- macrophages, Zbtb46+Langerin+ dendritic cells (DCs) and Ly6C+ inflammatory monocytes. Of those, the Langerin+ DC population stands out by its unique capacity to co-produce the cytokines IL-1β, IL-6 and IL-23, all of which promote IL-17 induction in response to C. albicans in the oral mucosa. The critical role of Langerin+ DCs for the innate IL-17 response was confirmed by depletion of this cellular subset in vivo, which compromised IL-17 induction during OPC. In conclusion, our work revealed key regulatory factors and their cellular sources of innate IL-17-dependent antifungal immunity in the oral mucosa.
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http://dx.doi.org/10.1371/journal.ppat.1007069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983869PMC
May 2018

Sequential BMP7/TGF-β1 signaling and microbiota instruct mucosal Langerhans cell differentiation.

J Exp Med 2018 02 17;215(2):481-500. Epub 2018 Jan 17.

The Institute of Dental Sciences, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

Mucosal Langerhans cells (LCs) originate from pre-dendritic cells and monocytes. However, the mechanisms involved in their in situ development remain unclear. Here, we demonstrate that the differentiation of murine mucosal LCs is a two-step process. In the lamina propria, signaling via BMP7-ALK3 promotes translocation of LC precursors to the epithelium. Within the epithelium, TGF-β1 finalizes LC differentiation, and ALK5 is crucial to this process. Moreover, the local microbiota has a major impact on the development of mucosal LCs, whereas LCs in turn maintain mucosal homeostasis and prevent tissue destruction. These results reveal the differential and sequential role of TGF-β1 and BMP7 in LC differentiation and highlight the intimate interplay of LCs with the microbiota.
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http://dx.doi.org/10.1084/jem.20171508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789418PMC
February 2018

Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells.

EBioMedicine 2018 Jan 20;27:293-303. Epub 2017 Dec 20.

Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4 T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.
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http://dx.doi.org/10.1016/j.ebiom.2017.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828466PMC
January 2018

In cutaneous leishmaniasis, induction of retinoic acid in skin-derived Langerhans cells is not sufficient for induction of parasite persistence-mediating regulatory T cells.

J Dermatol Sci 2017 Sep 17;87(3):307-309. Epub 2017 Jun 17.

Department of Dermatology, University Hospital of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2017.06.014DOI Listing
September 2017

Langerhans cells and NK cells cooperate in the inhibition of chemical skin carcinogenesis.

Oncoimmunology 2017;6(2):e1260215. Epub 2016 Nov 18.

Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck , Innsbruck, Austria.

Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFα mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFα-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis.
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http://dx.doi.org/10.1080/2162402X.2016.1260215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353916PMC
November 2016

TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity.

Proc Natl Acad Sci U S A 2017 02 6;114(8):E1480-E1489. Epub 2017 Feb 6.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany;

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8CD103 DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity.
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http://dx.doi.org/10.1073/pnas.1615065114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338403PMC
February 2017

Monitoring Skin Dendritic Cells in Steady State and Inflammation by Immunofluorescence Microscopy and Flow Cytometry.

Methods Mol Biol 2017 ;1559:37-52

Division of Experimental Dermatology, Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstrasse 35, A-6020, Innsbruck, Austria.

Skin dendritic cells (DC) are strategically positioned at the body's second largest epithelial border to the environment. Hence they are the first antigen presenting cells that encounter invading pathogens and environmental antigens, including contact sensitizers and carcinogens penetrating the skin. Moreover, DC have the unique ability to induce immunity or tolerance and thus take center stage in regulating innate and adaptive immune responses. Skin DC can be divided into several phenotypically and functionally distinct subtypes. The three main subsets are Langerin epidermal Langerhans cells (LC) and Langerin as well as Langerin dermal DC. In the steady state skin DC form a dense network to survey the periphery for pathogens and harmful substances breaching the cutaneous barrier. During inflammation DC become rapidly activated and start their migration to skin-draining lymph nodes where they initiate antigen-specific T cell responses. The homeostasis and mobilization of DC in the skin can be visualized by immunofluorescent staining of epidermal and dermal sheet preparations or skin sections. Here, we describe in detail how inflammation can be induced in the skin with tape stripping or FITC painting and how the skin DC network can be monitored using immunofluorescence microscopy and flow cytometry.
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http://dx.doi.org/10.1007/978-1-4939-6786-5_3DOI Listing
January 2018

Reproducibility Issues: Avoiding Pitfalls in Animal Inflammation Models.

Methods Mol Biol 2017 ;1559:1-17

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Straße 67, Mainz, D-55131, Germany.

In light of an enhanced awareness of ethical questions and ever increasing costs when working with animals in biomedical research, there is a dedicated and sometimes fierce debate concerning the (lack of) reproducibility of animal models and their relevance for human inflammatory diseases. Despite evident advancements in searching for alternatives, that is, replacing, reducing, and refining animal experiments-the three R's of Russel and Burch (1959)-understanding the complex interactions of the cells of the immune system, the nervous system and the affected tissue/organ during inflammation critically relies on in vivo models. Consequently, scientific advancement and ultimately novel therapeutic interventions depend on improving the reproducibility of animal inflammation models. As a prelude to the remaining hands-on protocols described in this volume, here, we summarize potential pitfalls of preclinical animal research and provide resources and background reading on how to avoid them.
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http://dx.doi.org/10.1007/978-1-4939-6786-5_1DOI Listing
January 2018

Monocyte-derived inflammatory Langerhans cells and dermal dendritic cells mediate psoriasis-like inflammation.

Nat Commun 2016 12 16;7:13581. Epub 2016 Dec 16.

Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland 20892, USA.

Dendritic cells (DCs) have been implicated in the pathogenesis of psoriasis but the roles for specific DC subsets are not well defined. Here we show that DCs are required for psoriasis-like changes in mouse skin induced by the local injection of IL-23. However, Flt3L-dependent DCs and resident Langerhans cells are dispensable for the inflammation. In epidermis and dermis, the critical DCs are TNF-producing and IL-1β-producing monocyte-derived DCs, including a population of inflammatory Langerhans cells. Depleting Ly6C blood monocytes reduces DC accumulation and the skin changes induced either by injecting IL-23 or by application of the TLR7 agonist imiquimod. Moreover, we find that IL-23-induced inflammation requires expression of CCR6 by DCs or their precursors, and that CCR6 mediates monocyte trafficking into inflamed skin. Collectively, our results imply that monocyte-derived cells are critical contributors to psoriasis through production of inflammatory cytokines that augment the activation of skin T cells.
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http://dx.doi.org/10.1038/ncomms13581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171657PMC
December 2016

IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively.

Immunity 2016 09 13;45(3):626-640. Epub 2016 Sep 13.

Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. Electronic address:

Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated "terminal selectors." Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs.
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http://dx.doi.org/10.1016/j.immuni.2016.08.013DOI Listing
September 2016

Dendritic cells as gatekeepers of tolerance.

Semin Immunopathol 2017 02 25;39(2):153-163. Epub 2016 Jul 25.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Dendritic cells (DC) are unique hematopoietic cells, linking innate and adaptive immune responses. In particular, they are considered as the most potent antigen presenting cells, governing both T cell immunity and tolerance. In view of their exceptional ability to present antigen and to interact with T cells, DC play distinct roles in shaping T cell development, differentiation and function. The outcome of the DC-T cell interaction is determined by the state of DC maturation, the type of DC subset, the cytokine microenvironment and the tissue location. Both regulatory T cells (Tregs) and DC are indispensable for maintaining central and peripheral tolerance. Over the past decade, accumulating data indicate that DC critically contribute to Treg differentiation and homeostasis.
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http://dx.doi.org/10.1007/s00281-016-0583-zDOI Listing
February 2017

IL-10 control of CD11c+ myeloid cells is essential to maintain immune homeostasis in the small and large intestine.

Oncotarget 2016 May;7(22):32015-30

Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.

Although IL-10 promotes a regulatory phenotype of CD11c+ dendritic cells and macrophages in vitro, the role of IL-10 signaling in CD11c+ cells to maintain intestinal tolerance in vivo remains elusive. To this aim, we generated mice with a CD11c-specific deletion of the IL-10 receptor alpha (Cd11ccreIl10rafl/fl). In contrast to the colon, the small intestine of Cd11ccreIl10rafl/fl mice exhibited spontaneous crypt hyperplasia, increased numbers of intraepithelial lymphocytes and lamina propria T cells, associated with elevated levels of T cell-derived IFNγ and IL-17A. Whereas naive mucosal T-cell priming was not affected and oral tolerance to ovalbumin was intact, augmented T-cell function in the lamina propria was associated with elevated numbers of locally dividing T cells, expression of T-cell attracting chemokines and reduced T-cell apoptosis. Upon stimulation, intestinal IL-10Rα deficient CD11c+ cells exhibited increased activation associated with enhanced IL-6 and TNFα production. Following colonization with Helicobacter hepaticus Cd11ccreIl10rafl/fl mice developed severe large intestinal inflammation characterized by infiltrating T cells and increased levels of Il17a, Ifng, and Il12p40. Altogether these findings demonstrate a critical role of IL-10 signaling in CD11c+ cells to control small intestinal immune homeostasis by limiting reactivation of local memory T cells and to protect against Helicobacter hepaticus-induced colitis.
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http://dx.doi.org/10.18632/oncotarget.8337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077993PMC
May 2016

Atopic dermatitis induces the expansion of thymus-derived regulatory T cells exhibiting a Th2-like phenotype in mice.

J Cell Mol Med 2016 May 2;20(5):930-8. Epub 2016 Mar 2.

Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.

Atopic dermatitis (AD) is a widespread inflammatory skin disease with an early onset, characterized by pruritus, eczematous lesions and skin dryness. This chronic relapsing disease is believed to be primarily a result of a defective epidermal barrier function associated with genetic susceptibility, immune hyper-responsiveness of the skin and environmental factors. Although the important role of abnormal immune reactivity in the pathogenesis of AD is widely accepted, the role of regulatory T cells (Tregs) remains elusive. We found that the Treg population is expanded in a mouse model of AD, i.e. mice topically treated with vitamin D3 (VitD). Moreover, mice with AD-like symptoms exhibit increased inducible T-cell costimulator (ICOS)-, cytotoxic T-lymphocyte antigen-4 (CTLA-4)- and Glycoprotein-A repetitions predominant receptor (GARP)-expressing Tregs in skin-draining lymph nodes. Importantly, the differentiation of Tregs into thymus-derived Tregs is favoured in our mouse model of AD. Emigrated skin-derived dendritic cells are required for Treg induction and Langerhans cells are responsible for the biased expansion of thymus-derived Tregs . Intriguingly, thymus-derived Tregs isolated from mice with AD-like symptoms exhibit a Th2 cytokine profile. Thus, AD might favour the expansion of pathogenic Tregs able to produce Th2 cytokines and to promote the disease instead of alleviating symptoms.
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http://dx.doi.org/10.1111/jcmm.12806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831369PMC
May 2016

Gradual development of psoriatic skin lesions by constitutive low-level expression of IL-17A.

Cell Immunol 2016 10 26;308:57-65. Epub 2015 Nov 26.

Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, The Netherlands; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany. Electronic address:

Psoriasis is a common chronic inflammatory skin disease restricted to humans. The understanding of its pathogenesis has long been hampered by the lack of suitable chronic mouse models. The cytokine IL-17A has emerged as a key player in epithelial immune responses and the defense against extracellular pathogens. Moreover, enhanced expression of IL-17A can turn pathologic and is closely associated with psoriasis. In this study, we generated a novel transgenic mouse model that recapitulates many characteristics of psoriasis. DC-IL-17A mice with constitutive low-level expression of IL-17A by CD11c cells gradually develop skin lesions during adult life. The lesions preferentially occur at sites of mechanical stress and exhibit macroscopic, histologic and genetic hallmarks of psoriatic plaques. Intriguingly, the age of disease onset depends on the levels of IL-17A and disruption of the epidermal barrier by tape-stripping triggers psoriatic plaque formation in the DC-IL-17A model. In summary, our results suggest that deregulated IL-17A together with epidermal trauma initiates skin inflammation and lesion formation in mice closely resembling plaque-type psoriasis. Due to the gradual development and chronic nature of disease, DC-IL-17A mice provide a unique tool to dissect the pathogenesis of human psoriasis and potentially could serve as a model to validate novel therapeutic strategies.
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http://dx.doi.org/10.1016/j.cellimm.2015.11.006DOI Listing
October 2016

Dendritic Cell-Specific Deletion of β-Catenin Results in Fewer Regulatory T-Cells without Exacerbating Autoimmune Collagen-Induced Arthritis.

PLoS One 2015 20;10(11):e0142972. Epub 2015 Nov 20.

Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Dendritic cells (DCs) are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating tolerogenic DC function in vivo remain largely unknown. The β-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of β-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of β-catenin specifically in DCs was achieved by crossing conditional knockout mice with a CD11c-Cre transgenic mouse line. Bone marrow-derived DCs (BMDCs) were generated and used to study the maturation profile of these cells in response to a TLR2 or TLR4 ligand stimulation. CIA was induced by intra-dermal immunization with 100 μg chicken type II collagen in complete Freund's adjuvant on days 0 and 21. CIA incidence and severity was monitored macroscopically and by histology. The T cell profile as well as their cytokine production were analysed by flow cytometry. Lack of β-catenin specifically in DCs did not affect the spontaneous, TLR2- or TLR4-induced maturation and activation of BMDCs or their cytokine production. Moreover, no effect on the incidence and severity of CIA was observed in mice lacking β-catenin in CD11c+ cells. A decreased frequency of splenic CD3+CD8+ T cells and of regulatory T cells (Tregs) (CD4+CD25highFoxP3+), but no changes in the frequency of splenic Th17 (CCR6+CXCR3-CCR4+), Th2 (CCR6-CXCR3-CCR4+) and Th1 (CCR6-CXCR3+CCR4-) cells were observed in these mice under CIA condition. Furthermore, the expression of IL-17A, IL-17F, IL-22, IL-4 or IFNγ was also not affected. Our data indicate that ablation of β-catenin expression in DCs did not alter the course and severity of CIA. We conclude that although deletion of β-catenin resulted in a lower frequency of Tregs, this decrease was not sufficient to aggravate the onset and severity of CIA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142972PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654567PMC
June 2016

Functional Specialization of Skin Dendritic Cell Subsets in Regulating T Cell Responses.

Front Immunol 2015 22;6:534. Epub 2015 Oct 22.

Department of Dermatology and Venereology, Division of Experimental Dermatology, Medical University of Innsbruck , Innsbruck , Austria.

Dendritic cells (DC) are a heterogeneous family of professional antigen-presenting cells classically recognized as most potent inducers of adaptive immune responses. In this respect, Langerhans cells have long been considered to be prototypic immunogenic DC in the skin. More recently this view has considerably changed. The generation of in vivo cell ablation and lineage tracing models revealed the complexity of the skin DC network and, in particular, established the existence of a number of phenotypically distinct Langerin(+) and negative DC populations in the dermis. Moreover, by now we appreciate that DC also exert important regulatory functions and are required for the maintenance of tolerance toward harmless foreign and self-antigens. This review summarizes our current understanding of the skin-resident DC system in the mouse and discusses emerging concepts on the functional specialization of the different skin DC subsets in regulating T cell responses. Special consideration is given to antigen cross-presentation as well as immune reactions toward contact sensitizers, cutaneous pathogens, and tumors. These studies form the basis for the manipulation of the human counterparts of the murine DC subsets to promote immunity or tolerance for the treatment of human disease.
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http://dx.doi.org/10.3389/fimmu.2015.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617171PMC
November 2015