TY - JOUR A1 - Arndt, Andreas A1 - Hoffacker, Peter A1 - Zellmer, Konstantin A1 - Goecer, Oktay A1 - Recks, Mascha S. A1 - Kuerten, Stefanie T1 - Conventional Housing Conditions Attenuate the Development of Experimental Autoimmune Encephalomyelitis JF - PLoS ONE N2 - BACKGROUND: The etiology of multiple sclerosis (MS) has remained unclear, but a causative contribution of factors outside the central nervous system (CNS) is conceivable. It was recently suggested that gut bacteria trigger the activation of CNS-reactive T cells and the development of demyelinative disease. METHODS: C57BL/6 (B6) mice were kept either under specific pathogen free or conventional housing conditions, immunized with the myelin basic protein (MBP)-proteolipid protein (PLP) fusion protein MP4 and the development of EAE was clinically monitored. The germinal center size of the Peyer's patches was determined by immunohistochemistry in addition to the level of total IgG secretion which was assessed by ELISPOT. ELISPOT assays were also used to measure MP4-specific T cell and B cell responses in the Peyer's patches and the spleen. Ear swelling assays were performed to determine the extent of delayed-type hypersensitivity reactions in specific pathogen free and conventionally housed mice. RESULTS: In B6 mice that were actively immunized with MP4 and kept under conventional housing conditions clinical disease was significantly attenuated compared to specific pathogen free mice. Conventionally housed mice displayed increased levels of IgG secretion in the Peyer's patches, while the germinal center formation in the gut and the MP4-specific TH17 response in the spleen were diminished after immunization. Accordingly, these mice displayed an attenuated delayed type hypersensitivity (DTH) reaction in ear swelling assays. CONCLUSIONS: The data corroborate the notion that housing conditions play a substantial role in the induction of murine EAE and suggest that the presence of gut bacteria might be associated with a decreased immune response to antigens of lower affinity. This concept could be of importance for MS and calls for caution when considering the therapeutic approach to treat patients with antibiotics." KW - B cells KW - secretion KW - multiple sclerosis KW - enzyme-linked immunoassays KW - Peyer's patches KW - gut bacteria KW - T cells KW - immune response Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119603 VL - 9 IS - 6 ER - TY - JOUR A1 - Badr, Mohammad A1 - McFleder, Rhonda L. A1 - Wu, Jingjing A1 - Knorr, Susanne A1 - Koprich, James B. A1 - Hünig, Thomas A1 - Brotchie, Jonathan M. A1 - Volkmann, Jens A1 - Lutz, Manfred B. A1 - Ip, Chi Wang T1 - Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson’s disease mice JF - Journal of Neuroinflammation N2 - Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson’s disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson’s disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson’s disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson’s disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson’s disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson’s disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson’s disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson’s disease patients. KW - Parkinson’s disease KW - neuroinflammation KW - T cells KW - regulatory T cells KW - neuroprotection Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300580 VL - 19 ER - TY - JOUR A1 - Beilhack, Andreas A1 - Chopra, Martin A1 - Kraus, Sabrina A1 - Schwinn, Stefanie A1 - Ritz, Miriam A1 - Mattenheimer, Katharina A1 - Mottok, Anja A1 - Rosenwald, Andreas A1 - Einsele, Hermann T1 - Non-Invasive Bioluminescence Imaging to Monitor the Immunological Control of a Plasmablastic Lymphoma-Like B Cell Neoplasia after Hematopoietic Cell Transplantation N2 - To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies. KW - B cells KW - T cells KW - Bioluminescence imaging KW - Bone marrow cells KW - Bone marrow transplantation KW - Cancer treatment KW - Spleen KW - Lymphomas Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111341 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 - 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 - Börtlein, Charlene A1 - Draeger, Annette A1 - Schoenauer, Roman A1 - Kuhlemann, Alexander A1 - Sauer, Markus A1 - Schneider-Schaulies, Sybille A1 - Avota, Elita T1 - The neutral sphingomyelinase 2 is required to polarize and sustain T Cell receptor signaling JF - Frontiers in Immunology N2 - By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca\(^{2+}\) mobilization and T cell proliferation. NSM-deficient T cells lack sustained CD3ζ and ZAP-70 phosphorylation and are unable to polarize and stabilize their microtubular system. We identified PKCζ as the key NSM downstream effector in this second wave of TCR signaling supporting dynamics of microtubule-organizing center (MTOC). Ceramide supplementation rescued PKCζ membrane recruitment and MTOC translocation in NSM-deficient cells. These findings identify the NSM as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components: CD3ζ, Zap70, and PKCζ, and functional immune synapses are organized and stabilized via MTOC polarization. KW - neutral sphingomyelinase 2 KW - T cells KW - ceramides KW - PKCζ, KW - the microtubule-organizing center Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176572 VL - 9 IS - 815 ER - TY - THES A1 - Chan, Gordon T1 - The Role of Vav-1, Vav-2 and Lsc in NK T cell development and NK cell cytotoxicity N2 - The hematopoietic-specific Rho-family GTP exchange factor (GEF) Vav-1 is a regulator of lymphocyte antigen receptor signaling and mediates normal maturation and activation of B and T cells. Recent findings suggest that Vav-1 also forms part of signaling pathways required for natural and antibody dependent cellular cytotoxicity (ADCC) of human NK cells. In this study, I show that Vav-1 is also expressed in murine NK cells. Vav-1-/- mice had normal numbers of splenic NK cells, and these displayed a similar expression profile of NK cell receptors as cells from wild type mice. Unexpectedly, IL-2-activated Vav-1-/- NK cells retained normal ADCC. Fc-receptor mediated activation of ERK, JNK, and p38 was also normal. In contrast, Vav-1-/- NK cells exhibited reduced natural cytotoxicity against EL4, C4.4.25, RMA and RMA/S. Together, these results demonstrate that Vav-1 is dispensable for mainstream NK cell development, but is required for NK cell natural cytotoxicity. Vav-2, a protein homologous to Vav-1 has also been implicated in NK cell functions. However, NK cells from Vav-2-/- mice have normal cytotoxic activities and NK cells that lack both Vav-1 and Vav-2 exhibit similar defect as Vav-1-/- cells. Thus Vav-2 has no apparent function in the development and the activation of NK cells. Although NK cell development is normal in Vav-1-/- mice, their numbers of NKT cells were dramatically diminished. Furthermore, NKT cells from Vav-1 mutant mice failed to produce IL-4 and IFNg following in vivo CD3 stimulation. A similar loss of NKT cells was observed in Vav-1-/-Vav-2-/- mice, but not in Vav-2-/- mice, suggesting that only Vav-1, and not Vav-2, is an essential regulator of NKT cell development and NK cell cytotoxicity. Similar to Vav-1, Lsc is a Rho GEF that is expressed specifically in the hematopoietic system. It contains a regulator of G-protein signaling (RGS) domain which negatively regulates the Ga12 and Ga13 subunits of G-protein coupled receptors (GPCRs). This study shows that NK and NKT cell development are normal in Lsc-/- mice. However, NK cells from mutant mice display enhanced cytotoxic responses towards a panel of tumor cells. These data implicate for the first time a RGS-containing Rho GEF in cytotoxic responses and suggest that Lsc down-modulate NK cell activation. N2 - Vav-1 ist ein spezifisch in hämatopoetischen Zellen exprimierter Guanin-Nukleotid-Exchange-Faktor (GEF) für Rho-GTPasen, der die Antigenrezeptor-vermittelte Signaltransduktion in Lymphocyten reguliert und essentiell für der Reifung und Aktivierung von B- und T-Zellen ist. Untersuchungen an menschlichen Zellen lassen vermuten, dass Vav1 auch für Antikörper-unabhängige, natürliche Zytotoxizität und die Antikörper-abhängige zellvermittelte Zytoxizität (ADCC) von „Natürlichen-Killerzellen“ (NK-Zellen) wichtig ist. In der vorliegenden Arbeit zeige ich, dass Vav-1 auch in murinen NK-Zellen exprimiert ist. Analysen von Vav-1-/--Mäuse zeigen eine normale Anzahl von NK-Zellen, die wiederum ein ähnliches Expressionsprofil von typischen NK-Zell-Rezeptoren im Vergleich zu wildtypischen Mäusen aufweisen. Die ADCC von Vav-1-/- NK-Zellen ist unverändert, wie auch die Fc-Rezeptor vermittelte Aktivierung von ERK, JNK und p38. Im Gegensatz dazu zeigen Vav-1-/- NK-Zellen eine reduzierte natürliche Cytotoxizität gegenüber EL4-, C4.4.25-, RMA- und RMA/S-Zielzellen. Vav-1 ist daher nicht für die Entwicklung, sondern für den Aufbau der natürlichen Cytotoxizität von NK-Zellen von Bedeutung. Für Vav-2 wurde ebenfalls eine Rolle in NK-Zellfunktionen wahrscheinlich gemacht. Dennoch zeigen Vav-2-/- Mäuse ein normales zytotoxisches Verhalten. NK-Zellen von Vav-1/Vav-2-doppeldefizienten Tieren weisen ähnliche Defekte wie NK-Zellen von Vav-1-defizienten Tieren. Somit besitzt Vav-2 keine entscheidende Funktion für die Entwicklung und Aktivierung von NK-Zellen. Im Gegensatz zu NK-Zellen ist die Anzahl der NKT-Zellen in Vav-1-/- Mäusen drastisch reduziert. Außerdem sind NKT-Zellen Vav-1-defizienter Mäuse nicht in der Lage IL-4 und INFg nach CD3-Stimulierung in vivo zu produzieren. Ein ähnlicher Verlust der NKT-Zell-Population wurde in Vav-1-/-- Vav-2-/--Mäusen beobachtet, nicht aber in Vav-2-/- Mäusen. Daher scheint nur Vav-1, nicht aber Vav-2, ein essentieller Regulator sowohl der NKT-Zell-Entwicklung als auch der NK-Zell-Cytotoxizität zu sein. Ein weiterer Rho-GEF, Lsc, ist ebenfalls spezifisch im hämatopoetischen System exprimiert. Lsc besitzt auch eine negativ-regulatorische RGS-Domäne (regulator of G-protein signaling) für die Ga12- und Ga13-Untereinheiten von G-Protein-gekoppelten Rezeptoren. NK- und NKT-Zellen von Lsc-defizienten Mäusen entwickeln sich normal, weisen aber eine erhöhte Cytotoxizität gegenüber einer Reihe von Tumor-Zellen auf. Diese Daten zeigen zum ersten mal die Beteiligung eines RGS-Rho-GEF an zytotoxischen Reaktionen und deuten auf eine negative Modulation der NK-Zell-Aktivierung durch Lsc hin. KW - Maus KW - Natürliche Killerzelle KW - Cytotoxizität KW - Vav KW - Lsc/p115 Rho GEF KW - NK cells KW - cytotoxicity KW - T cells Y1 - 2002 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-3645 ER - TY - JOUR A1 - Chopra, Martin A1 - Lang, Isabell A1 - Salzmann, Steffen A1 - Pachel, Christina A1 - Kraus, Sabrina A1 - Bäuerlein, Carina A. A1 - Brede, Christian A1 - Jordán Garrote, Ana-Laura A1 - Mattenheimer, Katharina A1 - Ritz, Miriam A1 - Schwinn, Stefanie A1 - Graf, Carolin A1 - Schäfer, Viktoria A1 - Frantz, Stefan A1 - Einsele, Hermann A1 - Wajant, Harald A1 - Beilhack, Andreas T1 - Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1 JF - PLoS ONE N2 - Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome. KW - Bioluminescence KW - cancer treatment KW - cell staining KW - cytokines KW - immune cells KW - metastasis KW - regulatory T cells KW - T cells Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97246 ER - TY - JOUR A1 - Cochain, Clement A1 - Chaudhari, Sweena M. A1 - Koch, Miriam A1 - Wiendl, Heinz A1 - Eckstein, Hans-Henning A1 - Zernecke, Alma T1 - Programmed Cell Death-1 Deficiency Exacerbates T Cell Activation and Atherogenesis despite Expansion of Regulatory T Cells in Atherosclerosis-Prone Mice JF - PLoS ONE N2 - T cell activation represents a double-edged sword in atherogenesis, as it promotes both pro-inflammatory T cell activation and atheroprotective Foxp3(+) regulatory T cell (Treg) responses. Here, we investigated the role of the co-inhibitory receptor programmed cell death-1 (PD-1) in T cell activation and CD4(+) T cell polarization towards pro-atherogenic or atheroprotective responses in mice. Mice deficient for both low density lipoprotein receptor and PD-1 (Ldlr(-/-)Pd1(-/-)) displayed striking increases in systemic CD4(+) and CD8(+) T cell activation after 9 weeks of high fat diet feeding, associated with an expansion of both pro-atherogenic IFNγ-secreting T helper 1 cells and atheroprotective Foxp3+ Tregs. Importantly, PD-1 deficiency did not affect Treg suppressive function in vitro. Notably, PD-1 deficiency exacerbated atherosclerotic lesion growth and entailed a massive infiltration of T cells in atherosclerotic lesions. In addition, aggravated hypercholesterolemia was observed in Ldlr(-/-)Pd1(-/-) mice. In conclusion, we here demonstrate that although disruption of PD-1 signaling enhances both pro- and anti-atherogenic T cell responses in Ldlr(-/-) mice, pro-inflammatory T cell activation prevails and enhances dyslipidemia, vascular inflammation and atherosclerosis. KW - nutritional deficiencies KW - atherosclerosis KW - spleen KW - aorta KW - diet KW - cytotoxic T cells KW - regulatory T cells KW - T cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119823 SN - 1932-6203 VL - 9 IS - 4 ER - TY - JOUR A1 - Eckert, Ina N. A1 - Ribechini, Eliana A1 - Jarick, Katja J. A1 - Strozniak, Sandra A1 - Potter, Sarah J. A1 - Beilhack, Andreas A1 - Lutz, Manfred B. T1 - VLA-1 Binding to Collagen IV Controls Effector T Cell Suppression by Myeloid-Derived Suppressor Cells in the Splenic Red Pulp JF - Frontiers in Immunology N2 - Myeloid-derived suppressor cells (MDSCs) represent a major population controlling T cell immune responses. However, little is known about their molecular requirements for homing and T cell interaction to mediate suppression. Here, we investigated the functional role of the homing and collagen IV receptor VLA-1 (α1β1-integrin) on in vitro GM-CSF generated murine MDSCs from wild-type (WT) and CD49a/α1-integrin (Itga1\(^{−/−}\)) gene-deficient mice. Here, we found that effector (Teff) but not naive (Tn) CD4\(^+\) T cells express VLA-1 and monocytes further up-regulated their expression after culture in GM-CSF when they differentiated into the monocytic subset of resting MDSCs (R-MDSCs). Subsequent activation of R-MDSCs by LPS+IFN-γ (A-MDSCs) showed increased in vitro suppressor potential, which was independent of VLA-1. Surprisingly, VLA-1 deficiency did not influence A-MDSC motility or migration on collagen IV in vitro. However, interaction times of Itga1\(^{−/−}\) A-MDSCs with Teff were shorter than with WT A-MDSCs on collagen IV but not on fibronectin substrate in vitro. After injection, A-MDSCs homed to the splenic red pulp where they co-localized with Teff and showed immediate suppression already after 6 h as shown by inhibition of T cell proliferation and induction of apoptosis. Injection of A-MDSCs from Itga1\(^{−/−}\) mice showed equivalent homing into the spleen but a reduced suppressive effect. Interaction studies of A-MDSCs with Teff in the subcapsular red pulp with intravital two-photon microscopy revealed also here that MDSC motility and migration parameters were not altered by VLA-1 deficiency, but the interaction times with Teff were reduced. Together, our data point to a new role of VLA-1 adhesion to collagen IV as a prerequisite for extended contact times with Teff required for suppression. KW - myeloid-derived suppressor cells (MDSCs) KW - T cells KW - VLA-1 KW - homing KW - spleen Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222671 SN - 1664-3224 VL - 11 ER - TY - JOUR A1 - Fehrholz, Markus A1 - Glaser, Kirsten A1 - Seidenspinner, Silvia A1 - Ottensmeier, Barbara A1 - Curstedt, Tore A1 - Speer, Christian P. A1 - Kunzmann, Steffen T1 - Impact of the New Generation Reconstituted Surfactant CHF5633 on Human CD4\(^+\) Lymphocytes JF - PLoS One N2 - Background Natural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP-) B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown. Aim The aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4\(^+\) lymphocytes. Methods Purified human CD4\(^+\) T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®). Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry. Results Neither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4\(^+\) lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were significantly increased in CHF5633 exposed CD4\(^+\) lymphocytes. Conclusion For the first time, the immunomodulatory capacity of CHF5633 on CD4\(^+\) lymphocytes was evaluated. CHF5633 did not show any cytotoxicity on CD4\(^+\) cells. Moreover, our in vitro data indicate that CHF5633 does not exert unintended pro-inflammatory effects on non-activated and activated CD4+ T cells. As far as anti-inflammatory cytokines are concerned, it might lack an overall reductive ability in comparison to animal-derived surfactants, potentially leaving pro- and anti-inflammatory cytokine response in balance. KW - lymphocytes KW - surfactants KW - flow cytometry KW - monocytes KW - RNA isolation KW - T cells KW - cytokines KW - inflammation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146419 VL - 11 IS - 4 ER - TY - JOUR A1 - Grotemeyer, Alexander A1 - Fischer, Judith F. A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Blum, Robert A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson’s disease JF - Journal of Neuroinflammation N2 - Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4\(^+\) and CD8\(^+\) T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD. KW - neurodegeneration KW - movement disorder KW - neuroinflammation KW - Parkinson’s disease KW - inflammasome KW - dopaminergic cells KW - NLRP3 KW - MCC950 KW - microglia KW - T cells Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357652 VL - 20 ER - TY - JOUR A1 - Grotemeyer, Alexander A1 - McFleder, Rhonda Leah A1 - Wu, Jingjing A1 - Wischhusen, Jörg A1 - Ip, Chi Wang T1 - Neuroinflammation in Parkinson’s disease – putative pathomechanisms and targets for disease-modification JF - Frontiers in Immunology N2 - Parkinson’s disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD. KW - Parkinson’s disease KW - neuroinflammation KW - T cells KW - microglia KW - neurodegeneration KW - animal models KW - inflammatory cascades Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-274665 SN - 1664-3224 VL - 13 ER - TY - JOUR A1 - Haake, Markus A1 - Haack, Beatrice A1 - Schäfer, Tina A1 - Harter, Patrick N. A1 - Mattavelli, Greta A1 - Eiring, Patrick A1 - Vashist, Neha A1 - Wedekink, Florian A1 - Genssler, Sabrina A1 - Fischer, Birgitt A1 - Dahlhoff, Julia A1 - Mokhtari, Fatemeh A1 - Kuzkina, Anastasia A1 - Welters, Marij J. P. A1 - Benz, Tamara M. A1 - Sorger, Lena A1 - Thiemann, Vincent A1 - Almanzar, Giovanni A1 - Selle, Martina A1 - Thein, Klara A1 - Späth, Jacob A1 - Gonzalez, Maria Cecilia A1 - Reitinger, Carmen A1 - Ipsen-Escobedo, Andrea A1 - Wistuba-Hamprecht, Kilian A1 - Eichler, Kristin A1 - Filipski, Katharina A1 - Zeiner, Pia S. A1 - Beschorner, Rudi A1 - Goedemans, Renske A1 - Gogolla, Falk Hagen A1 - Hackl, Hubert A1 - Rooswinkel, Rogier W. A1 - Thiem, Alexander A1 - Romer Roche, Paula A1 - Joshi, Hemant A1 - Pühringer, Dirk A1 - Wöckel, Achim A1 - Diessner, Joachim E. A1 - Rüdiger, Manfred A1 - Leo, Eugen A1 - Cheng, Phil F. A1 - Levesque, Mitchell P. A1 - Goebeler, Matthias A1 - Sauer, Markus A1 - Nimmerjahn, Falk A1 - Schuberth-Wagner, Christine A1 - Felten, Stefanie von A1 - Mittelbronn, Michel A1 - Mehling, Matthias A1 - Beilhack, Andreas A1 - van der Burg, Sjoerd H. A1 - Riedel, Angela A1 - Weide, Benjamin A1 - Dummer, Reinhard A1 - Wischhusen, Jörg T1 - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment JF - Nature Communications N2 - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. KW - cancer microenvironment KW - immunotherapy KW - T cells KW - tumour immunology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333 VL - 14 ER - TY - JOUR A1 - Kader, Hidaya A. A1 - Azeem, Muhammad A1 - Jwayed, Suhib A. A1 - Al-Shehhi, Aaesha A1 - Tabassum, Attia A1 - Ayoub, Mohammed Akli A1 - Hetta, Helal F. A1 - Waheed, Yasir A1 - Iratni, Rabah A1 - Al-Dhaheri, Ahmed A1 - Muhammad, Khalid T1 - Current insights into immunology and novel therapeutics of atopic dermatitis JF - Cells N2 - Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes. KW - atopic dermatitis KW - immune system KW - T cells KW - B cells KW - keratinocytes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241008 SN - 2073-4409 VL - 10 IS - 6 ER - TY - JOUR A1 - Karulin, Alexey Y. A1 - Karacsony, Kinga A1 - Zhang, Wenji A1 - Targoni, Oleg S. A1 - Moldova, Ioana A1 - Dittrich, Marcus A1 - Sundararaman, Srividya A1 - Lehmann, Paul V. T1 - ELISPOTs produced by CD8 and CD4 cells follow Log Normal size distribution permitting objective counting JF - Cells N2 - Each positive well in ELISPOT assays contains spots of variable sizes that can range from tens of micrometers up to a millimeter in diameter. Therefore, when it comes to counting these spots the decision on setting the lower and the upper spot size thresholds to discriminate between non-specific background noise, spots produced by individual T cells, and spots formed by T cell clusters is critical. If the spot sizes follow a known statistical distribution, precise predictions on minimal and maximal spot sizes, belonging to a given T cell population, can be made. We studied the size distributional properties of IFN-γ, IL-2, IL-4, IL-5 and IL-17 spots elicited in ELISPOT assays with PBMC from 172 healthy donors, upon stimulation with 32 individual viral peptides representing defined HLA Class I-restricted epitopes for CD8 cells, and with protein antigens of CMV and EBV activating CD4 cells. A total of 334 CD8 and 80 CD4 positive T cell responses were analyzed. In 99.7% of the test cases, spot size distributions followed Log Normal function. These data formally demonstrate that it is possible to establish objective, statistically validated parameters for counting T cell ELISPOTs. KW - ELISPOT KW - software KW - IFN-γ KW - IL-17 KW - T cells KW - Normal Distribution KW - spot size KW - gating KW - cytokines KW - IL-2 KW - IL-4 KW - IL-5 KW - CD8 KW - CD4 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149648 VL - 4 IS - 1 ER - TY - JOUR A1 - Kim, Mia A1 - Grimmig, Tanja A1 - Grimm, Martin A1 - Lazariotou, Maria A1 - Meier, Eva A1 - Rosenwald, Andreas A1 - Tsaur, Igor A1 - Blaheta, Roman A1 - Heemann, Uwe A1 - Germer, Christoph-Thomas A1 - Waaga-Gasser, Ana Maria A1 - Gasser, Martin T1 - Expression of Foxp3 in Colorectal Cancer but Not in Treg Cells Correlates with Disease Progression in Patients with Colorectal Cancer JF - PLoS ONE N2 - Background Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression. KW - T cells KW - gene regulation KW - alternative splicing KW - measles virus KW - T cell receptors KW - reverse transcriptase-polymerase chain reaction KW - TCR signaling cascade KW - cell cycle and cell division Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130340 VL - 8 IS - 1 ER - TY - THES A1 - Koch, Miriam T1 - Role of Coagulation Factor XII in Atherosclerosis T1 - Rolle des Koagulationsfaktors XII in der Atherosklerose N2 - Atherosclerosis is considered a chronic inflammatory disease of the arterial vessel wall which is not only modulated by innate and adaptive immune responses but also by factors of the blood coagulation system. In general hypercoagulability seems to increase the development and progression of experimental atherosclerosis in mice on an atherogenic background. In addition, the great majority of coagulation proteins including coagulation factor XII (FXII) have been detected in early and advanced human atherosclerotic lesions supporting the cross-link between the coagulation system and atherosclerosis. Moreover, FXII has been detected in close proximity to macrophages, foam cells and smooth muscle cells in these lesions and has been demonstrated to be functionally active in human plaques. Although these data indicate that factor XII may play a role in atherogenesis a direct contribution of FXII to atherogenesis has not been addressed experimentally to date. Furthermore, clinical studies examining the function of FXII in vascular disease have yielded conflicting results. Hence, in order to investigate the function of coagulation factor XII in atherosclerosis apolipoprotein E and FXII-deficient (F12\(^{-/-}\) apoE\(^{-/-}\)) mice were employed. Compared to F12\(^{+/+}\)apoE\(^{-/-}\) controls, atherosclerotic lesion formation was reduced in F12\(^{-/-}\)apoE\(^{-/-}\) mice, associated with diminished systemic T-cell activation and Th1-cell polarization after 12 weeks of high fat diet. Moreover, a significant decrease in plasma levels of complement factor C5a was evidenced in F12\(^{-/-}\)apoE\(^{-/-}\) mice. Interestingly, C5a increased the production of interleukin-12 (IL-12) in dendritic cells (DCs) and enhanced their capacity to trigger antigen-specific interferon-gamma (IFNγ) production in OTII CD4\(^+\) T cells in vitro. Importantly, a reduction in frequencies of IL-12 expressing splenic DCs from atherosclerotic F12\(^{-/-}\)apoE\(^{-/-}\) versus F12\(^{+/+}\)apoE\(^{-/-}\) mice was observed in vivo, accompanied by a diminished splenic Il12 transcript expression and significantly reduced IL-12 serum levels. Consequently, these data reveal FXII to play an important role in atherosclerotic lesion formation and to promote DC-induced and systemic IL 12 expression as well as pro-inflammatory T-cell responses likely at least in part via the activation of the complement system. N2 - Die Arteriosklerose wird als eine chronisch entzündliche Erkrankung der arteriellen Gefäßwand angesehen, welche nicht nur durch Antworten des angeborenen und erworbenen Immunsystems, sondern auch durch Faktoren des Blutgerinnungssystems beeinflusst wird. Aus Tierstudien weiß man, dass Hyperkoagulabilität im Allgemeinen die Entwicklung und das Fortschreiten der Arteriosklerose in Mäusen mit atherogenem Hintergrund steigert. Ferner wurde die Mehrheit der Blutgerinnungsproteine inklusive des Koagulationsfaktors XII (FXII) in frühen und fortgeschrittenen arteriosklerotischen Läsionen in Menschen nachgewiesen, was eine mögliche Verbindung zwischen Koagulationssystem und Arteriosklerose untermauert. Darüber hinaus wurde der FXII in diesen Läsionen im unmittelbaren Umfeld von Makrophagen, Schaumzellen und glatten Muskelzellen nachgewiesen und dessen funktionelle Aktivität in humanen Plaques aufgezeigt. Obwohl diese Daten eine Funktion von FXII in der Arteriosklerose nahelegen, wurde eine direkte Beteiligung von FXII an der Atherogenese bislang experimentell noch nicht untersucht. Ferner erzielten klinische Studien, welche die Funktion von FXII in Gefäßerkrankungen untersuchten, widersprüchliche Resultate. Um die Funktion des Koagulationsfaktors XII in der Atherosklerose zu untersuchen, wurden daher Apolipoprotein E und FXII-defiziente (F12\(^{-/-}\)apoE\(^{-/-}\)) Mäuse eingesetzt. Die Ausbildung arteriosklerotischer Läsionen war in F12\(^{+/+}\)apoE\(^{-/-}\) Mäusen im Vergleich zu F12\(^{+/+}\)apoE\(^{-/-}\) Kontrollen reduziert. Dies ging mit einer verringerten systemischen T-Zell Aktivierung und Th1-Zell Polarisierung nach 12-wöchiger atherogener Diät einher. Ferner konnte eine signifikante Reduktion der C5a-Plasmaspiegel in F12\(^{-/-}\)apoE\(^{-/-}\) Mäusen nachgewiesen werden. Interessanterweise konnte C5a die Interleukin-12 (IL 12) Produktion in dendritischen Zellen (DCs) steigern, sowie deren Fähigkeit erhöhen, eine antigen-spezifische Interferon-gamma (IFNγ) Produktion in vitro, in OTII CD4\(^+\) T-Zellen zu induzieren. Insbesondere konnte in vivo eine Reduktion IL-12-exprimierender DCs in Milzen arteriosklerotischer F12\(^{-/-}\)apoE\(^{-/-}\) im Vergleich zu F12\(^{+/+}\)apoE\(^{-/-}\) Mäusen beobachtet werden, welche mit einer verminderten Expression an Il12 Transkripten in der Milz und signifikant reduzierten IL-12 Serumspiegeln einherging. Zusammenfassend zeigen diese Daten, dass FXII eine wichtige Rolle in der Bildung arteriosklerotischer Läsionen spielt und die DC-vermittelte und systemische IL-12 Expression, sowie pro-inflammatorische T-Zell Antworten, vermutlich teilweise über eine Aktivierung des Komplementsystems, fördert. KW - Gerinnungsfaktor XII KW - Arteriosklerose KW - coagulation factor XII KW - atherosclerosis KW - T cells KW - dendritic cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97850 ER - TY - JOUR A1 - Kuznetsov, Nikolai V. A1 - Almuzzaini, Bader A1 - Kritikou, Joanna S. A1 - Baptista, Marisa A. P. A1 - Oliveira, Mariana M. S. A1 - Keszei, Marton A1 - Snapper, Scott B. A1 - Percipalle, Piergiorgio A1 - Westerberg, Lisa S. T1 - Nuclear Wiskott-Aldrich syndrome protein co-regulates T cell factor 1-mediated transcription in T cells JF - Genome Medicine N2 - Background The Wiskott–Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell development remains incompletely defined. Methods We performed WASp chromatin immunoprecipitation and deep sequencing (ChIP-seq) in thymocytes and spleen CD4\(^+\) T cells. Results WASp was enriched at genic and intergenic regions and associated with the transcription start sites of protein-coding genes. Thymocytes and spleen CD4\(^+\) T cells showed 15 common WASp-interacting genes, including the gene encoding T cell factor (TCF)12. WASp KO thymocytes had reduced nuclear TCF12 whereas thymocytes expressing constitutively active WASp\(^{L272P}\) and WASp\(^{I296T}\) had increased nuclear TCF12, suggesting that regulated WASp activity controlled nuclear TCF12. We identify a putative DNA element enriched in WASp ChIP-seq samples identical to a TCF1-binding site and we show that WASp directly interacted with TCF1 in the nucleus. Conclusions These data place nuclear WASp in proximity with TCF1 and TCF12, essential factors for T cell development. KW - Medicine KW - WASp KW - T cells KW - ChIP-seq KW - Wiskott-Aldrich syndrome KW - TCF1 KW - TCF12 KW - Nucleus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173486 VL - 9 ER - TY - JOUR A1 - Lauruschkat, Chris D. A1 - Page, Lukas A1 - Etter, Sonja A1 - Weis, Philipp A1 - Gamon, Florian A1 - Kraus, Sabrina A1 - Einsele, Hermann A1 - Wurster, Sebastian A1 - Loeffler, Juergen T1 - T-Cell Immune Surveillance in Allogenic Stem Cell Transplant Recipients: Are Whole Blood–Based Assays Ready to Challenge ELISPOT? JF - Open Forum Infectious Diseases N2 - We compared the feasibility of 4 cytomegalovirus (CMV)- and Aspergillus-reactive T-cell immunoassay protocols in allogenic stem cell transplant recipients. While enzyme-linked immunospot performed best overall, logistically advantageous whole blood–based assays performed comparably in patients with less severe lymphocytopenia. CMV-induced interferon-gamma responses correlated strongly across all protocols and showed high concordance with serology. KW - immunoassay KW - biomarker KW - aspergillosis KW - cytomegalovirus KW - T cells KW - cytokines KW - flow cytometry KW - ELISPOT Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363164 VL - 8 ER -