TY - JOUR A1 - Boivin, Valérie A1 - Beyersdorf, Niklas A1 - Palm, Dieter A1 - Nikolaev, Viacheslav O. A1 - Schlipp, Angela A1 - Müller, Justus A1 - Schmidt, Doris A1 - Kocoski, Vladimir A1 - Kerkau, Thomas A1 - Hünig, Thomas A1 - Ertl, Georg A1 - Lohse, Martin J. A1 - Jahns, Roland T1 - Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by \(Anti-β_1-Adrenoceptor\) Antibodies in a Human-Analogous Rat Model JF - PLoS One N2 - Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the \(β_1\) adrenergic receptor \((β_1EC2)\). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195–225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking \(β_1EC2\) (\(β_1EC2-CP\), 1.0 mg/kg every 4 weeks) or administration of the \(β_1-blocker\) bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received \(β_1EC2-CP/bisoprolol\) co-treatment. We found that \(β_1EC2-CP\) prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, \(β_1EC2-CP\) mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free \(anti-β_1EC2-antibodies\) and by targeting \(β_1EC2\)-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful \(anti-β_1EC2-antibodies\) and also selectively depletes memory B-cells involved in the production of such antibodies. Treatment with immuno-modulating cyclopeptides alone or as an add-on to \(β_1\)-blockade represents a promising new therapeutic option in immune-mediated heart failure. KW - memory B cells KW - antibodies KW - T cells KW - B cells KW - heart KW - heart failure KW - kidneys KW - enzyme-linked immunoassays Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126028 VL - 10 IS - 2 ER - TY - JOUR A1 - Beyersdorf, Niklas A1 - Werner, Sandra A1 - Wolf, Nelli A1 - Herrmann, Thomas A1 - Kerkau, Thomas T1 - Characterization of a New Mouse Model for Peripheral T Cell Lymphoma in Humans JF - PLoS One N2 - Peripheral T cell lymphomas (PTCLs) are associated with a poor prognosis due to often advanced disease at the time of diagnosis and due to a lack of efficient therapeutic options. Therefore, appropriate animal models of PTCL are vital to improve clinical management of this disease. Here, we describe a monoclonal CD8\(^+\) CD4\(^−\) αβ T cell receptor Vβ2\(^+\) CD28\(^+\) T cell lymphoma line, termed T8-28. T8-28 cells were isolated from an un-manipulated adult BALB/c mouse housed under standard pathogen-free conditions. T8-28 cells induced terminal malignancy upon adoptive transfer into syngeneic BALB/c mice. Despite intracellular expression of the cytotoxic T cell differentiation marker granzyme B, T8-28 cells appeared to be defective with respect to cytotoxic activity as read-out in vitro. Among the protocols tested, only addition of interleukin 2 in vitro could partially compensate for the in vivo micro-milieu in promoting growth of the T8-28 lymphoma cells. KW - T cells KW - cytotoxic T cells KW - mouse models KW - interleukins KW - cell staining KW - lymphomas KW - fluorescence-activated cell sorting KW - lymph nodes Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137946 VL - 6 IS - 12 ER - TY - THES A1 - Beyersdorf, Niklas T1 - Phänotyp und Funktion KLRG1-exprimierender Lymphozyten der Maus T1 - Phenotype and function of KLRG1-expressing lymphocytes of the mouse N2 - Die Reifung, Differenzierung und Funktion von Lymphozyten wird maßgeblich von aktivierenden und inhibitorischen Zelloberflächenrezeptoren reguliert. "Killer cell Lectin-like receptor G1" (KLRG1) ist ein Typ-II-Transmembranprotein, dessen Expression auf Subpopulationen von T-Lymphozyten und Natürlichen Killerzellen beschränkt ist. Die vorliegende Arbeit hatte zum Ziel, die differentielle Expression und mögliche Funktion von KLRG1 auf diesen Zellen im Maussystem zu charakterisieren. Mit Hilfe zellbiologischer Untersuchungsmethoden konnte gezeigt werden, dass die KLRG1-Expressionsfrequenz mit dem Reifegrad der Zellen korreliert. Frühere Beobachtungen, wonach KLRG1 durch Erkennung eigener Klasse-I-Moleküle des Haupthistokompatibilitätskomplexes (MHC) über inhibitorische Rezeptoren der Ly49-Familie induziert wird, konnten auf klassische Klasse-I-Moleküle und neue Ly49-Familienmitglieder ausgeweitet werden. Ferner belegen Daten dieser Arbeit, dass reife NK-Zellen die KLRG1-Expressionsfrequenz in verschiedenen lymphoiden Organen dem Klasse-I-Niveau der umgebenden Zellen anpassen können und dass T- und B-Lymphozyten möglicherweise eine zentrale Rolle hierbei spielen. Somit stellt KLRG1 einen NK-Zellrezeptor dar, dessen Expression durch Ly49-Rezeptorengagement dynamisch reguliert wird. Es ist möglich, dass KLRG1 kompensatorische (ko-)inhibitorische Eigenschaften besitzt, die für die Aufrechterhaltung der Selbsttoleranz von NK-Zellen von Bedeutung sind. Unter den CD8-T-Zellen identifiziert ein polyklonales abT-Zellrezeptorrepertoire und die Expression von CD8 als ab-Heterodimer den 2-3%igen Anteil an KLRG1+ Zellen als konventionelle T-Zellen thymischen Ursprungs. Umfangreiche phänotypische und funktionelle Analysen ergaben, dass KLRG1-exprimierende CD8-Zellen sich aus ca. 20% proinflammatorischer Effektorzellen und ca. 80% Gedächtniszellen zusammensetzen. Aufgrund von Daten der Arbeitsgruppe Pircher scheint das Zellteilungsvermögen letzterer ausgeschöpft zu sein. Demzufolge markiert KLRG1 eine neue Subpopulation von CD8-T-Zellen, der sowohl Effektorzellen, als auch "replikativ seneszente" Gedächtniszellen angehören. Abschließende Untersuchungen ergaben, dass KLRG1 interessanterweise auch von 1-2% der CD4+ T-Zellen exprimiert wird und dass die KLRG1+ CD4-T-Zellen zum Großteil CD25 koexprimieren. Funktionelle Anschlußexperimente zeigten, dass es sich bei diesen Zellen um regulatorische T-Zellen handelt. Zusammenfassend kennzeichnet KLRG1-Expression eine Subpopulationen von NK-Zellen, die körpereigene Zellen über Klasse-I erkennen können, eine Untergruppe von Effektor- und seneszenten CD8-T-Zellen sowie neuartige regulatorische CD4-T-Zellen. N2 - The maturation, differentiation and function of lymphocytes is crucially regulated by activating and inhibitory cell surface receptors. "Killer cell lectin-like receptor G1" (KLRG1) is a type-II transmembrane protein, which is expressed on subpopulations of T cells and Natural Killer cells. The aim of this work was to characterise the differential expression and possible function of KLRG1 on these cells in the mouse. Cell biological assays revealed that the expression frequency of KLRG1 and the maturity of the cells are positively correlated. The earlier finding that KLRG1 expression is induced after recognition of self class I molecules of the Major Histocompatibility Complex (MHC) by inhibitory receptors of the Ly49 family could be extended to classical class I molecules and to novel members of the Ly49 family. Moreover, the data contained in this work provide evidence that mature NK cells are capable of adapting KLRG1 expression frequencies to the level of class I expression on surrounding cells in the respective lymphoid organ and that T and B lymphocytes probably play a central role in this process. KLRG1 expression on NK cells, thus, is subject to dynamic regulation via engagement of Ly49 receptors. Moreover, it is possible that KLRG1 is endowed with compensatory (co-)inhibitory properties which are important for maintaining self-tolerance of NK cells. Among CD8 T cells it is the polyclonal ab T cell receptor repertoire and the expression of CD8 as an ab heterodimer which indicates thymic origin of the 2-3% KLRG1+ cells. Extensive phenotypical and functional analyses revealed that KLRG1-expressing CD8 cells are a mixture of about 20% pro-inflammatory effector cells and about 80% memory cells. According to data generated in the group of Hanspeter Pircher the latter have lost the potential to undergo further cell divisions. Therefore, KLRG1 is a marker for a novel subpopulation of CD8 T cells consisting of, both, effector cells and "senescent" memory cells. In final experiments, KLRG1 expression was detected on 1-2% of CD4+ T cells with the majority of KLRG1+ CD4 T cells co-expressing CD25. Subsequent functional studies revealed that these cells are regulatory T cells. In summary, KLRG1 expression marks a subpopulation of NK cells, which are capable of recognising other cells via class I molecules, a subset of effector and senescent CD8 T cells as wells as novel regulatory CD4 T cells. KW - NK-Zellen KW - T-Zellen KW - inhibitorische Rezeptoren KW - KLRG1 KW - NK cells KW - T cells KW - inhibitory receptors KW - KLRG1 Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-17550 ER - TY - JOUR A1 - Langenhorst, Daniela A1 - Haack, Stephanie A1 - Göb, Selina A1 - Uri, Anna A1 - Lühder, Fred A1 - Vanhove, Bernhard A1 - Hünig, Thomas A1 - Beyersdorf, Niklas T1 - CD28 costimulation of T helper 1 cells enhances cytokine release in vivo JF - Frontiers in Immunology N2 - Compared to naive T cells, differentiated T cells are thought to be less dependent on CD28 costimulation for full activation. To revisit the role of CD28 costimulation in mouse T cell recall responses, we adoptively transferred in vitro generated OT-II T helper (Th) 1 cells into C57BL/6 mice (Thy1.2\(^{+}\)) and then either blocked CD28–ligand interactions with Fab fragments of the anti-CD28 monoclonal antibody (mAb) E18 or deleted CD28 expression using inducible CD28 knock-out OT-II mice as T cell donors. After injection of ovalbumin protein in adjuvant into the recipient mice we observed that systemic interferon (IFN)γ release strongly depended on CD28 costimulation of the Th1 cells, while secondary clonal expansion was not reduced in the absence of CD28 costimulation. For human memory CD4\(^{+}\) T cell responses we also noted that cytokine release was reduced upon inhibition of CD28 costimulation. Together, our data highlight the so far underestimated role of CD28 costimulation for the reactivation of fully differentiated CD4\(^{+}\) T cells. KW - CD4\(^{+}\) T helper cells KW - T helper 1 cells KW - antigenic recall KW - CD28 costimulation KW - cytokine secretion KW - mouse KW - human Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176726 VL - 9 IS - 1060 ER - TY - JOUR A1 - Wiese, Teresa A1 - Dennstädt, Fabio A1 - Hollmann, Claudia A1 - Stonawski, Saskia A1 - Wurst, Catherina A1 - Fink, Julian A1 - Gorte, Erika A1 - Mandasari, Putri A1 - Domschke, Katharina A1 - Hommers, Leif A1 - Vanhove, Bernard A1 - Schumacher, Fabian A1 - Kleuser, Burkard A1 - Seibel, Jürgen A1 - Rohr, Jan A1 - Buttmann, Mathias A1 - Menke, Andreas A1 - Schneider-Schaulies, Jürgen A1 - Beyersdorf, Niklas T1 - Inhibition of acid sphingomyelinase increases regulatory T cells in humans JF - Brain Communications N2 - Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro. KW - acid sphingomyelinase KW - antidepressants KW - major depression KW - regulatory T cells KW - sphingolipids Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259868 VL - 3 IS - 2 ER - TY - JOUR A1 - Ickrath, Pascal A1 - Sprügel, Lisa A1 - Beyersdorf, Niklas A1 - Scherzad, Agmal A1 - Hagen, Rudolf A1 - Hackenberg, Stephan T1 - Detection of Candida albicans-Specific CD4+ and CD8+ T Cells in the Blood and Nasal Mucosa of Patients with Chronic Rhinosinusitis JF - Journal of Fungi N2 - Candida albicans is ubiquitously present, and colonization in the nose and oral cavity is common. In healthy patients, it usually does not act as a pathogen, but in some cases can cause diseases. The influence of C. albicans as a trigger of T cell activation on the pathogenesis of chronic rhinosinusitis (CRS) is controversial, and its exact role is not clear to date. The aim of the present study was to detect and characterize C. albicans-specific CD4+ and CD8+ T cells in patients with CRS, with and without nasal polyps. Tissue and blood samples were collected from patients suffering from chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP), and from healthy controls. A peptide pool derived from C. albicans antigen was added to tissue and blood samples. After 6 days, lymphocytes were analyzed by multicolor flow cytometry. Activation was assessed by the intracellular marker Ki-67, and the cytokine secretion was measured. Tissue CD8+ T cells of CRSsNP patients showed a significantly higher proportion of Ki-67+ cells after activation with C. albicans antigen compared to peripheral blood CD8+ T cells. Cytokine secretion in response to C. albicans antigen was similar for all study groups. In this study, C. albicans-specific CD4+ and CD8+ T cells were detected in peripheral blood and mucosal tissue in all study groups. In patients suffering from CRSsNP, C. albicans-specific CD8+ T cells were relatively enriched in the nasal mucosa, suggesting that they might play a role in the pathogenesis of CRSsNP. KW - Candida albicans KW - chronic rhinosinusitis KW - T cell activation KW - nasal polyps Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239671 SN - 2309-608X VL - 7 IS - 6 ER - TY - JOUR A1 - Uri, Anna A1 - Werner, Sandra A1 - Lühder, Fred A1 - Hünig, Thomas A1 - Kerkau, Thomas A1 - Beyersdorf, Niklas T1 - Protection of mice from acute graft-versus-host disease requires CD28 co-stimulation on donor CD4\(^{+}\) Foxp3\(^{+}\) regulatory T Cells JF - Frontiers in Immunology N2 - Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell plus T cell transplantation (allo-HSCT). In this study, we investigated the requirement for CD28 co-stimulation of donor CD4\(^{+}\) conventional (CD4\(^{+}\)CD25\(^{-}\)Foxp3\(^{-}\), Tconv) and regulatory (CD4\(^{+}\)CD25\(^{+}\)Foxp3\(^{+}\), Treg) T cells in aGvHD using tamoxifen-inducible CD28 knockout (iCD28KO) or wild-type (wt) littermates as donors of CD4\(^{+}\) Tconv and Treg. In the highly inflammatory C57BL/6 into BALB/c allo-HSCT transplantation model, CD28 depletion on donor CD4\(^{+}\) Tconv reduced clinical signs of aGvHD, but did not significantly prolong survival of the recipient mice. Selective depletion of CD28 on donor Treg did not abrogate protection of recipient mice from aGvHD until about day 20 after allo-HSCT. Later, however, the pool of CD28-depleted Treg drastically declined as compared to wt Treg. Consequently, only wt, but not CD28-deficient, Treg were able to continuously suppress aGvHD and induce long-term survival of the recipient mice. To our knowledge, this is the first study that specifically evaluates the impact of CD28 expression on donor Treg in aGvHD. Moreover, the delayed kinetics of aGvHD lethality after transplantation of iCD28KO Treg provides a novel animal model for similar disease courses found in patients after allo-HSCT. KW - co-stimulation, KW - inducible deletion KW - regulatory T cells KW - acute graft-versus-host disease KW - CD28 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158469 VL - 8 IS - 721 ER - TY - JOUR A1 - Grafen, Anika A1 - Schumacher, Fabian A1 - Chithelen, Janice A1 - Kleuser, Burkhard A1 - Beyersdorf, Niklas A1 - Schneider-Schaulies, Jürgen T1 - Use of acid ceramidase and sphingosine kinase inhibitors as antiviral compounds against measles virus infection of lymphocytes in vitro JF - Frontiers in Cell and Developmental Biology N2 - As structural membrane components and signaling effector molecules sphingolipids influence a plethora of host cell functions, and by doing so also the replication of viruses. Investigating the effects of various inhibitors of sphingolipid metabolism in primary human peripheral blood lymphocytes (PBL) and the human B cell line BJAB we found that not only the sphingosine kinase (SphK) inhibitor SKI-II, but also the acid ceramidase inhibitor ceranib-2 efficiently inhibited measles virus (MV) replication. Virus uptake into the target cells was not grossly altered by the two inhibitors, while titers of newly synthesized MV were reduced by approximately 1 log (90%) in PBL and 70–80% in BJAB cells. Lipidomic analyses revealed that in PBL SKI-II led to increased ceramide levels, whereas in BJAB cells ceranib-2 increased ceramides. SKI-II treatment decreased sphingosine-1-phosphate (S1P) levels in PBL and BJAB cells. Furthermore, we found that MV infection of lymphocytes induced a transient (0.5–6 h) increase in S1P, which was prevented by SKI-II. Investigating the effect of the inhibitors on the metabolic (mTORC1) activity we found that ceranib-2 reduced the phosphorylation of p70 S6K in PBL, and that both inhibitors, ceranib-2 and SKI-II, reduced the phosphorylation of p70 S6K in BJAB cells. As mTORC1 activity is required for efficient MV replication, this effect of the inhibitors is one possible antiviral mechanism. In addition, reduced intracellular S1P levels affect a number of signaling pathways and functions including Hsp90 activity, which was reported to be required for MV replication. Accordingly, we found that pharmacological inhibition of Hsp90 with the inhibitor 17-AAG strongly impaired MV replication in primary PBL. Thus, our data suggest that treatment of lymphocytes with both, acid ceramidase and SphK inhibitors, impair MV replication by affecting a number of cellular activities including mTORC1 and Hsp90, which alter the metabolic state of the cells causing a hostile environment for the virus. KW - measles virus KW - sphingolipids KW - acid ceramidase KW - acid ceramidase inhibitor ceranib-2 KW - sphingosine kinase KW - sphingosine kinase inhibitor SKI-II Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196099 SN - 2296-634X VL - 7 IS - 218 ER - TY - JOUR A1 - Haack, Stephanie A1 - Baiker, Sarah A1 - Schlegel, Jan A1 - Sauer, Markus A1 - Sparwasser, Tim A1 - Langenhorst, Daniela A1 - Beyersdorf, Niklas T1 - Superagonistic CD28 stimulation induces IFN‐γ release from mouse T helper 1 cells in vitro and in vivo JF - European Journal of Immunology N2 - Like human Th1 cells, mouse Th1 cells also secrete IFN‐γ upon stimulation with a superagonistic anti‐CD28 monoclonal antibody (CD28‐SA). Crosslinking of the CD28‐SA via FcR and CD40‐CD40L interactions greatly increased IFN‐γ release. Our data stress the utility of the mouse as a model organism for immune responses in humans. KW - CD28 KW - Th1 cells KW - cytokine release KW - interferon γ KW - Superagonistic antibody Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239028 VL - 51 IS - 3 SP - 738 EP - 741 ER - TY - JOUR A1 - Dasari, Prasad A1 - Koleci, Naile A1 - Shopova, Iordana A. A1 - Wartenberg, Dirk A1 - Beyersdorf, Niklas A1 - Dietrich, Stefanie A1 - Sahagún-Ruiz, Alfredo A1 - Figge, Marc Thilo A1 - Skerka, Christine A1 - Brakhage, Axel A. A1 - Zipfel, Peter F. T1 - Enolase from Aspergillus fumigatus is a moonlighting protein that binds the human plasma complement proteins factor H, FHL-1, C4BP, and plasminogen JF - Frontiers in Immunology N2 - The opportunistic fungal pathogen Aspergillus fumigatus can cause severe infections, particularly in immunocompromised individuals. Upon infection, A. fumigatus faces the powerful and directly acting immune defense of the human host. The mechanisms on how A. fumigatus evades innate immune attack and complement are still poorly understood. Here, we identify A. fumigatus enolase, AfEno1, which was also characterized as fungal allergen, as a surface ligand for human plasma complement regulators. AfEno1 binds factor H, factor-H-like protein 1 (FHL-1), C4b binding protein (C4BP), and plasminogen. Factor H attaches to AfEno1 via two regions, via short conserved repeats (SCRs) 6–7 and 19–20, and FHL-1 contacts AfEno1 via SCRs 6–7. Both regulators when bound to AfEno1 retain cofactor activity and assist in C3b inactivation. Similarly, the classical pathway regulator C4BP binds to AfEno1 and bound to AfEno1; C4BP assists in C4b inactivation. Plasminogen which binds to AfEno1 via lysine residues is accessible for the tissue-type plasminogen activator (tPA), and active plasmin cleaves the chromogenic substrate S2251, degrades fibrinogen, and inactivates C3 and C3b. Plasmin attached to swollen A. fumigatus conidia damages human A549 lung epithelial cells, reduces the cellular metabolic activity, and induces cell retraction, which results in exposure of the extracellular matrix. Thus, A. fumigatus AfEno1 is a moonlighting protein and virulence factor which recruits several human regulators. The attached human regulators allow the fungal pathogen to control complement at the level of C3 and to damage endothelial cell layers and tissue components. KW - complement factor H KW - moonlighting KW - immune evasion KW - plasminogen KW - blocking phagocytosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195612 SN - 1664-3224 VL - 10 ER - TY - JOUR A1 - Morbach, Caroline A1 - Beyersdorf, Niklas A1 - Kerkau, Thomas A1 - Ramos, Gustavo A1 - Sahiti, Floran A1 - Albert, Judith A1 - Jahns, Roland A1 - Ertl, Georg A1 - Angermann, Christiane E. A1 - Frantz, Stefan A1 - Hofmann, Ulrich A1 - Störk, Stefan T1 - Adaptive anti-myocardial immune response following hospitalization for acute heart failure JF - ESC Heart Failure N2 - Aims It has been hypothesized that cardiac decompensation accompanying acute heart failure (AHF) episodes generates a pro-inflammatory environment boosting an adaptive immune response against myocardial antigens, thus contributing to progression of heart failure (HF) and poor prognosis. We assessed the prevalence of anti-myocardial autoantibodies (AMyA) as biomarkers reflecting adaptive immune responses in patients admitted to the hospital for AHF, followed the change in AMyA titres for 6 months after discharge, and evaluated their prognostic utility. Methods and results AMyA were determined in n = 47 patients, median age 71 (quartiles 60; 80) years, 23 (49%) female, and 24 (51%) with HF with preserved ejection fraction, from blood collected at baseline (time point of hospitalization) and at 6 month follow-up (visit F6). Patients were followed for 18 months (visit F18). The prevalence of AMyA increased from baseline (n = 21, 45%) to F6 (n = 36, 77%; P < 0.001). At F6, the prevalence of AMyA was higher in patients with HF with preserved ejection fraction (n = 21, 88%) compared with patients with reduced ejection fraction (n = 14, 61%; P = 0.036). During the subsequent 12 months after F6, that is up to F18, patients with newly developed AMyA at F6 had a higher risk for the combined endpoint of death or rehospitalization for HF (hazard ratio 4.79, 95% confidence interval 1.13–20.21; P = 0.033) compared with patients with persistent or without AMyA at F6. Conclusions Our results support the hypothesis that AHF may induce patterns of adaptive immune responses. More studies in larger populations and well-defined patient subgroups are needed to further clarify the role of the adaptive immune system in HF progression. KW - adaptive immune response KW - acute heart failure KW - anti-myocardial KW - autoantibody KW - inflammation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258907 VL - 8 IS - 4 ER - TY - JOUR A1 - Bergfeld, Arne A1 - Dasari, Prasad A1 - Werner, Sandra A1 - Hughes, Timothy R. A1 - Song, Wen-Chao A1 - Hortschansky, Peter A1 - Brakhage, Axel A. A1 - Hünig, Thomas A1 - Zipfel, Peter F. A1 - Beyersdorf, Niklas T1 - Direct binding of the pH-regulated Protein 1 (Pra1) from Candida albicans inhibits cytokine secretion by mouse CD4\(^{+}\) T cells JF - Frontiers in Microbiology N2 - Opportunistic infections with the saprophytic yeast Candida albicans are a major cause of morbidity in immunocompromised patients. While the interaction of cells and molecules of innate immunity with C. albicans has been studied to great depth, comparatively little is known about the modulation of adaptive immunity by C. albicans. In particular, direct interaction of proteins secreted by C. albicans with CD4\(^{+}\) T cells has not been studied in detail. In a first screening approach, we identified the pH-regulated antigen 1 (Pra1) as a molecule capable of directly binding to mouse CD4\(^{+}\) T cells in vitro. Binding of Pra1 to the T cell surface was enhanced by extracellular Zn\(^{2+}\) ions which Pra1 is known to scavenge from the host in order to supply the fungus with Zn\(^{2+}\). In vitro stimulation assays using highly purified mouse CD4\(^{+}\) T cells showed that Pra1 increased proliferation of CD4\(^{+}\) T cells in the presence of plate-bound anti-CD3 monoclonal antibody. In contrast, secretion of effector cytokines such as IFNγ and TNF by CD4\(^{+}\) T cells upon anti-CD3/ anti-CD28 mAb as well as cognate antigen stimulation was reduced in the presence of Pra1. By secreting Pra1 C. albicans, thus, directly modulates and partially controls CD4\(^{+}\) T cell responses as shown in our in vitro assays. KW - Candida albicans KW - pH-regulated antigen 1 (Pra1) KW - CD4\(^{+}\) T cells KW - immune evasion KW - cytokine secretion Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158274 VL - 8 IS - 844 ER - TY - JOUR A1 - Hollmann, Claudia A1 - Wiese, Teresa A1 - Dennstädt, Fabio A1 - Fink, Julian A1 - Schneider-Schaulies, Jürgen A1 - Beyersdorf, Niklas T1 - Translational approaches targeting ceramide generation from sphingomyelin in T cells to modulate immunity in humans JF - Frontiers in Immunology N2 - In T cells, as in all other cells of the body, sphingolipids form important structural components of membranes. Due to metabolic modifications, sphingolipids additionally play an active part in the signaling of cell surface receptors of T cells like the T cell receptor or the co-stimulatory molecule CD28. Moreover, the sphingolipid composition of their membranes crucially affects the integrity and function of subcellular compartments such as the lysosome. Previously, studying sphingolipid metabolism has been severely hampered by the limited number of analytical methods/model systems available. Besides well-established high resolution mass spectrometry new tools are now available like novel minimally modified sphingolipid subspecies for click chemistry as well as recently generated mouse mutants with deficiencies/overexpression of sphingolipid-modifying enzymes. Making use of these tools we and others discovered that the sphingolipid sphingomyelin is metabolized to ceramide to different degrees in distinct T cell subpopulations of mice and humans. This knowledge has already been translated into novel immunomodulatory approaches in mice and will in the future hopefully also be applicable to humans. In this paper we are, thus, summarizing the most recent findings on the impact of sphingolipid metabolism on T cell activation, differentiation, and effector functions. Moreover, we are discussing the therapeutic concepts arising from these insights and drugs or drug candidates which are already in clinical use or could be developed for clinical use in patients with diseases as distant as major depression and chronic viral infection. KW - sphingolipids KW - CD4+ T cells KW - regulatory T cells (Treg) KW - CD8+ T cells KW - anti-depressant drug Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198806 SN - 1664-3224 VL - 10 IS - 2363 ER - TY - JOUR A1 - Dasari, Prasad A1 - Shopova, Iordana A. A1 - Stroe, Maria A1 - Wartenberg, Dirk A1 - Martin-Dahse, Hans A1 - Beyersdorf, Niklas A1 - Hortschansky, Peter A1 - Dietrich, Stefanie A1 - Cseresnyés, Zoltán A1 - Figge, Marc Thilo A1 - Westermann, Martin A1 - Skerka, Christine A1 - Brakhage, Axel A. A1 - Zipfel, Peter F. T1 - Aspf2 From Aspergillus fumigatus Recruits Human Immune Regulators for Immune Evasion and Cell Damage JF - Frontiers in Immunology N2 - The opportunistic fungal pathogen Aspergillus fumigatus can cause life-threatening infections, particularly in immunocompromised patients. Most pathogenic microbes control host innate immune responses at the earliest time, already before infiltrating host immune cells arrive at the site of infection. Here, we identify Aspf2 as the first A. fumigatus Factor H-binding protein. Aspf2 recruits several human plasma regulators, Factor H, factor-H-like protein 1 (FHL-1), FHR1, and plasminogen. Factor H contacts Aspf2 via two regions located in SCRs6–7 and SCR20. FHL-1 binds via SCRs6–7, and FHR1 via SCRs3–5. Factor H and FHL-1 attached to Aspf2-maintained cofactor activity and assisted in C3b inactivation. A Δaspf2 knockout strain was generated which bound Factor H with 28% and FHL-1 with 42% lower intensity. In agreement with less immune regulator acquisition, when challenged with complement-active normal human serum, Δaspf2 conidia had substantially more C3b (>57%) deposited on their surface. Consequently, Δaspf2 conidia were more efficiently phagocytosed (>20%) and killed (44%) by human neutrophils as wild-type conidia. Furthermore, Aspf2 recruited human plasminogen and, when activated by tissue-type plasminogen activator, newly generated plasmin cleaved the chromogenic substrate S2251 and degraded fibrinogen. Furthermore, plasmin attached to conidia damaged human lung epithelial cells, induced cell retraction, and caused matrix exposure. Thus, Aspf2 is a central immune evasion protein and plasminogen ligand of A. fumigatus. By blocking host innate immune attack and by disrupting human lung epithelial cell layers, Aspf2 assists in early steps of fungal infection and likely allows tissue penetration. KW - complement KW - blocking opsonization KW - phagocytosis KW - acquisition of host regulators KW - immune evasion Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197013 SN - 1664-3224 VL - 9 IS - 1635 ER - TY - JOUR A1 - Berges, Carsten A1 - Kerkau, Thomas A1 - Werner, Sandra A1 - Wolf, Nelli A1 - Winter, Nadine A1 - Hünig, Thomas A1 - Einsele, Hermann A1 - Topp, Max S. A1 - Beyersdorf, Niklas T1 - Hsp90 inhibition ameliorates CD4\(^{+}\) T cell-mediated acute Graft versus Host disease in mice JF - Immunity, Inflammation and Disease N2 - Introduction: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication. Methods: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4\(^{+}\) T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4\(^{+}\) and CD8\(^{+}\) T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4\(^{+}\) T cells with a relative resistance of CD4\(^{+}\) regulatory and CD8\(^{+}\) T cells toward Hsp90 inhibition. Conclusions: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect. KW - Hsp90 KW - leukemia KW - acute Graft versus Host Disease KW - Graft versus Tumor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168318 VL - 4 IS - 4 ER - TY - JOUR A1 - Langenhorst, Daniela A1 - Tabares, Paula A1 - Gulde, Tobias A1 - Becklund, Bryan R. A1 - Berr, Susanne A1 - Surh, Charles D. A1 - Beyersdorf, Niklas A1 - Hünig, Thomas T1 - Self-recognition sensitizes mouse and human regulatory T cells to low-dose CD28 superagonist stimulation JF - Frontiers in Immunology N2 - In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4\(^{+}\) T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro, the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self-peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self-recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity. KW - D665 KW - regulatory T cells KW - self-reactivity KW - autoimmunity KW - CD28 superagonists KW - TGN1412 KW - TAB08 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159387 VL - 8 IS - 1985 ER - TY - JOUR A1 - Collenburg, Lena A1 - Beyersdorf, Niklas A1 - Wiese, Teresa A1 - Arenz, Christoph A1 - Saied, Essa M. A1 - Becker-Flegler, Katrin Anne A1 - Schneider-Schaulies, Sibylle A1 - Avota, Elita T1 - The activity of the neutral sphingomyelinase is important in T cell recruitment and directional migration JF - Frontiers in Immunology N2 - Breakdown of sphingomyelin as catalyzed by the activity of sphingomyelinases profoundly affects biophysical properties of cellular membranes which is particularly important with regard to compartmentalization of surface receptors and their signaling relay. As it is activated both upon TCR ligation and co-stimulation in a spatiotemporally controlled manner, the neutral sphingomyelinase (NSM) has proven to be important in T cell activation, where it appears to play a particularly important role in cytoskeletal reorganization and cell polarization. Because these are important parameters in directional T cell migration and motility in tissues, we analyzed the role of the NSM in these processes. Pharmacological inhibition of NSM interfered with early lymph node homing of T cells in vivo indicating that the enzyme impacts on endothelial adhesion, transendothelial migration, sensing of chemokine gradients or, at a cellular level, acquisition of a polarized phenotype. NSM inhibition reduced adhesion of T cells to TNF-α/IFN-γ activated, but not resting endothelial cells, most likely via inhibiting high-affinity LFA-1 clustering. NSM activity proved to be highly important in directional T cell motility in response to SDF1-α, indicating that their ability to sense and translate chemokine gradients might be NSM dependent. In fact, pharmacological or genetic NSM ablation interfered with T cell polarization both at an overall morphological level and redistribution of CXCR4 and pERM proteins on endothelial cells or fibronectin, as well as with F-actin polymerization in response to SDF1-α stimulation, indicating that efficient directional perception and signaling relay depend on NSM activity. Altogether, these data support a central role of the NSM in T cell recruitment and migration both under homeostatic and inflamed conditions by regulating polarized redistribution of receptors and their coupling to the cytoskeleton. KW - LFA-1 KW - neutral sphingomyelinase KW - T cell migration KW - ceramide KW - polarization KW - adhesion Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158944 VL - 8 IS - 1007 ER - TY - JOUR A1 - Avota, Elita A1 - Bodem, Jochen A1 - Chithelen, Janice A1 - Mandasari, Putri A1 - Beyersdorf, Niklas A1 - Schneider-Schaulies, Jürgen T1 - The Manifold Roles of Sphingolipids in Viral Infections JF - Frontiers in Physiology N2 - Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach. KW - sphingolipid KW - ceramide KW - sphingosine-1-phosphate KW - plasma membrane KW - virus entry KW - virus replication KW - virus budding Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246975 SN - 1664-042X VL - 12 ER - TY - JOUR A1 - Eder, Sascha A1 - Hollmann, Claudia A1 - Mandasari, Putri A1 - Wittmann, Pia A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Fink, Julian A1 - Seibel, Jürgen A1 - Schneider-Schaulies, Jürgen A1 - Stigloher, Christian A1 - Beyersdorf, Niklas A1 - Dembski, Sofia T1 - Synthesis and characterization of ceramide-containing liposomes as membrane models for different T cell subpopulations JF - Journal of Functional Biomaterials N2 - A fine balance of regulatory (T\(_{reg}\)) and conventional CD4\(^+\) T cells (T\(_{conv}\)) is required to prevent harmful immune responses, while at the same time ensuring the development of protective immunity against pathogens. As for many cellular processes, sphingolipid metabolism also crucially modulates the T\(_{reg}\)/T\(_{conv}\) balance. However, our understanding of how sphingolipid metabolism is involved in T cell biology is still evolving and a better characterization of the tools at hand is required to advance the field. Therefore, we established a reductionist liposomal membrane model system to imitate the plasma membrane of mouse T\(_{reg}\) and T\(_{conv}\) with regards to their ceramide content. We found that the capacity of membranes to incorporate externally added azide-functionalized ceramide positively correlated with the ceramide content of the liposomes. Moreover, we studied the impact of the different liposomal preparations on primary mouse splenocytes in vitro. The addition of liposomes to resting, but not activated, splenocytes maintained viability with liposomes containing high amounts of C\(_{16}\)-ceramide being most efficient. Our data thus suggest that differences in ceramide post-incorporation into T\(_{reg}\) and T\(_{conv}\) reflect differences in the ceramide content of cellular membranes. KW - liposome KW - ceramide KW - cell membrane model Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286130 SN - 2079-4983 VL - 13 IS - 3 ER - TY - JOUR A1 - Halder, Luke D. A1 - Abdelfatah, Mahmoud A. A1 - Jo, Emeraldo A. H. A1 - Jacobsen, Ilse D. A1 - Westermann, Martin A1 - Beyersdorf, Niklas A1 - Lorkowski, Stefan A1 - Zipfel, Peter F. A1 - Skerka, Christine T1 - Factor H binds to extracellular DNA traps released from human blood monocytes in response to Candida albicans JF - Frontiers in Immunology N2 - Upon systemic infection with human pathogenic yeast Candida albicans (C. albicans), human monocytes and polymorph nuclear neutrophilic granulocytes are the first immune cells to respond and come into contact with C. albicans. Monocytes exert immediate candidacidal activity and inhibit germination, mediate phagocytosis, and kill fungal cells. Here, we show that human monocytes spontaneously respond to C. albicans cells via phagocytosis, decondensation of nuclear DNA, and release of this decondensed DNA in the form of extracellular traps (called monocytic extracellular traps: MoETs). Both subtypes of monocytes (CD14\(^{++}\)CD16\(^−\)/CD14\(^+\)CD16\(^+\)) formed MoETs within the first hours upon contact with C. albicans. MoETs were characterized by the presence of citrullinated histone, myeloperoxidase, lactoferrin, and elastase. MoETs were also formed in response to Staphylococcus aureus and Escherichia coli, indicating a general reaction of monocytes to infectious microbes. MoET induction differs from extracellular trap formation in macrophages as MoETs are not triggered by simvastatin, an inhibitor of cholesterol synthesis and inducer of extracellular traps in macrophages. Extracellular traps from both monocytes and neutrophils activate complement and C3b is deposited. However, factor H (FH) binds via C3b to the extracellular DNA, mediates cofactor activity, and inhibits the induction of the inflammatory cytokine interleukin-1 beta in monocytes. Altogether, the results show that human monocytes release extracellular DNA traps in response to C. albicans and that these traps finally bind FH via C3b to presumably support clearance without further inflammation. KW - Candida KW - monocytes KW - DNA traps KW - MPO KW - factor H Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181127 VL - 7 ER -