TY  - THES
A1  - Ashour, DiyaaEldin
T1  - Kinetics and timing of IL-12 production by dendritic cells for Th1 polarization \(in\) \(vivo\)
T1  - Kinetik und zeitlicher Ablauf der IL-12-Produktion durch Dendritische Zellen für die Th1 Polarisierung \(in\) \(vivo\)
N2  - Auf Dendritische Zellen (DCs) basierende Vakzinen hängen von der Qualität der DC-Reifung ab, um Antigenpräsentation, Kostimulation, Lymphknotenmigration und, im Faller einer T-Helfer-1 (Th1) Polarisierung, die Freisetzung von IL-12 zu induzieren. Die Herstellung des heterodimeren IL-12p70 durch injizierte DC wurde klassisch als Schlüsselfaktor beschrieben, der für die Erzeugung einer polarisierten Th1 Immunreaktion erforderlich ist. Dennoch induzieren DCs, die IL-12 nicht ausscheiden können (z. B. nach Reifung des Cytokin-Cocktails), Th1 polarisierte Immunantwortenin Mäusen und Menschen. Da zuvor auch beschrieben wurde, dass DCs in der Lage sind, andere DCs auf Bystander-Weise zu aktivieren, haben wir hier die DC-Quelle der IL-12 Produktion für die Th1-Polarisation in einem murinen DC-Vakzinemodell untersucht. Die Migration der injizierten, aus murinem Knochenmark generierten DCs (BM-DCs) war für den Antigentransport in den Lymphknoten wesentlich. Sie trugen jedoch nur teilweise zur Antigenpräsentation bei und induzierten nur einen nicht polarisierten Th0-Zustand der T-Zellen, die IL-2 produzierten, aber kein IFN-. Stattdessen deuten die Daten daraufhin, dass endogene dermale migrierende XCR1+ DCs als Bystander-DCs zur Antigenpräsentation beitragen und IL-12 für die Th1 Polarisation bereitstellten. Die genetische Ablation von migrierenden DCs und speziell von XCR1+ migrierenden DCs hebt das Th1 Priming vollständig auf, Die Kinetik der Wechselwirkungen in den drainierenden Lymphknoten erfolgt schrittweise, indem i) injizierte DCs mit verwandten T-Zellen, ii) injizierte DCs mit Bystander XCR1+ DCs und iii) Bystander XCR1+ DCs mit T-Zellen in Kontakt treten. Das Transkriptom der Bystander-DCs zeigte eine Herunterregulierung von Treg- und Th2/Th9-induzierenden Genen und eine Hochregulierung der für die Th1- Induktion erforderlichen Gene. Zusammen zeigen diese Daten, dass injizierte reife migrierende BM-DCs das T-Zell-Priming und die Bystander-DC-Aktivierung steuern, nicht jedoch die Th1-Polarisation, die durch endogene IL-12p70+ XCR1+ Bystander-DCs vermittelt wird. Unsere Ergebnisse sind von Bedeutung für klinische Studien mit Vakzine-DCs, bei denen endogene DCs durch eine Chemotherapie funktionell beeinträchtigt werden können.
N2  - Dendritic cell (DC) based vaccines rely on the quality of DC maturation to induce antigen presentation, co-stimulation, lymph node migration and the release of heterodimeric IL-12p70 in case of T helper type-1 cell (Th1) polarization. In contrast, DCs that cannot secrete IL-12p70 (e.g. after cytokine cocktail maturation) readily induce Th1 cells when injected into mice and humans. Since it was also previously suggested that DCs are capable of activating other DCs in a bystander fashion, we tested here for the DC source of IL-12p70 for Th1 polarization in a murine DC vaccination model. Migration of the injected murine bone marrow-derived DCs (BM-DCs) was essential for antigen delivery to the lymph node. However, they contributed only partially to antigen presentation, and induced a non-polarized Th0 state of the cognate T cells producing IL-2 but no IFN-. Instead, endogenous dermal migratory XCR1+ cDC1s underwent re-programming by the injected BM-DCs to acquire bystander antigen presentation and IL-12 release for Th1 polarization in the lymph node. Genetic deficiency of migratory DCs and specifically of XCR1+ migratory DCs completely abolished Th1 priming. The kinetic of cell interactions in the draining lymph nodes appeared step-wise as i) injected DCs with cognate T cells, ii) injected DCs with bystander XCR1+ DCs, and iii) bystander XCR1+ DCs with T cells. The transcriptome of the bystander DCs showed a down-regulation of Treg and Th2/Th9 inducing genes, and up-regulation of genes required for Th1 instruction. Together, these data show that injected mature lymph node migratory BM-DCs direct T cell priming and bystander DC activation, but not Th1 polarization which is mediated by endogenous IL-12p70+ XCR1+ migratory bystander DCs. Our results are of importance for clinical DC-based vaccinations against tumors where endogenous DCs may be functionally impaired by chemotherapy.
KW  - Immunologie
KW  - Dendritic cells
KW  - Dendritische Zellen
KW  - Vakzinen
KW  - Vaccine
KW  - IL-12p70
KW  - Dendritische Zelle
KW  - Immunology
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179483
ER  - 
TY  - JOUR
A1  - Delgobo, Murilo
A1  - Heinrichs, Margarete
A1  - Hapke, Nils
A1  - Ashour, DiyaaElDin
A1  - Appel, Marc
A1  - Srivastava, Mugdha
A1  - Heckel, Tobias
A1  - Spyridopoulos, Ioakim
A1  - Hofmann, Ulrich
A1  - Frantz, Stefan
A1  - Ramos, Gustavo Campos
T1  - Terminally Differentiated CD4\(^+\) T Cells Promote Myocardial Inflammaging
JF  - Frontiers in Immunology
N2  - The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4\(^+\) T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4\(^+\) T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4\(^+\) T cell compartment was primarily composed of naïve cells defined as CCR7\(^+\)CD45RO\(^-\). However, when transplanted into young lymphocyte-deficient mice, CD4\(^+\) T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7\(^-\) CD45RO\(^+\)) and terminally-differentiated phenotypes (CCR7\(^-\)CD45RO\(^-\)), as typically seen in elderly. Differentiated CD4\(^+\) T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4\(^+\) T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4\(^+\) T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.
KW  - CD4+ T-cells
KW  - myocardial aging
KW  - inflammaging
KW  - NSG animals
KW  - immunosenescence
KW  - lymphocytes
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229612
SN  - 1664-3224
VL  - 12
ER  - 
TY  - JOUR
A1  - Vendelova, Emilia
A1  - Ashour, Diyaaeldin
A1  - Blank, Patrick
A1  - Erhard, Florian
A1  - Saliba, Antoine-Emmanuel
A1  - Kalinke, Ulrich
A1  - Lutz, Manfred B.
T1  - Tolerogenic transcriptional signatures of steady-state and pathogen-induced dendritic cells
JF  - Frontiers in Immunology
N2  - Dendritic cells (DCs) are key directors of tolerogenic and immunogenic immune responses. During the steady state, DCs maintain T cell tolerance to self-antigens by multiple mechanisms including inducing anergy, deletion, and Treg activity. All of these mechanisms help to prevent autoimmune diseases or other hyperreactivities. Different DC subsets contribute to pathogen recognition by expression of different subsets of pattern recognition receptors, including Toll-like receptors or C-type lectins. In addition to the triggering of immune responses in infected hosts, most pathogens have evolved mechanisms for evasion of targeted responses. One such strategy is characterized by adopting the host's T cell tolerance mechanisms. Understanding these tolerogenic mechanisms is of utmost importance for therapeutic approaches to treat immune pathologies, tumors and infections. Transcriptional profiling has developed into a potent tool for DC subset identification. Here, we review and compile pathogen-induced tolerogenic transcriptional signatures from mRNA profiling data of currently available bacterial- or helminth-induced transcriptional signatures. We compare them with signatures of tolerogenic steady-state DC subtypes to identify common and divergent strategies of pathogen induced immune evasion. Candidate molecules are discussed in detail. Our analysis provides further insights into tolerogenic DC signatures and their exploitation by different pathogens.
KW  - bacteria
KW  - helminths
KW  - immune evasion
KW  - mycobacteria
KW  - transcriptional profiling
KW  - tolerogenic dendritic cells
KW  - steady-state dendritic cells
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175636
VL  - 9
IS  - 333
ER  - 
TY  - JOUR
A1  - Silva-Vilches, Cinthia
A1  - Pletinckx, Katrien
A1  - Lohnert, Miriam
A1  - Pavlovic, Vladimir
A1  - Ashour, Diyaaeldin
A1  - John, Vini
A1  - Vendelova, Emilia
A1  - Kneitz, Susanne
A1  - Zhou, Jie
A1  - Chen, Rena
A1  - Reinheckel, Thomas
A1  - Mueller, Thomas D.
A1  - Bodem, Jochen
A1  - Lutz, Manfred B.
T1  - Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion
JF  - PLoS ONE
N2  - 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.
KW  - small interfering RNAs
KW  - toxins
KW  - regulatory T cells
KW  - T cells
KW  - cytokines
KW  - cholera
KW  - cell differentiation
KW  - immune evasion
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158244
VL  - 12
IS  - 7
ER  -