Lisa Göschl
Medical University of Vienna
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Featured researches published by Lisa Göschl.
Arthritis & Rheumatism | 2013
Michael Bonelli; E. Ferner; Lisa Göschl; Stephan Blüml; Anastasiya Hladik; Thomas Karonitsch; Hans P. Kiener; Ruth A. Byrne; Birgit Niederreiter; Carl-Walter Steiner; Eva Rath; Michael Bergmann; Josef S Smolen; Clemens Scheinecker
OBJECTIVE The binding of abatacept (CTLA-4Ig) to the B7 ligands CD80 and CD86 prevents the engagement of CD28 on T cells and thereby prevents effector T cell activation. In addition, a direct effect of CTLA-4Ig on antigen-presenting cells (APCs) could contribute to the therapeutic effect. To further elucidate the mechanism of CTLA-4Ig, we performed phenotype and functional analyses of APCs in patients with rheumatoid arthritis (RA) before and after the initiation of CTLA-4Ig therapy. METHODS Peripheral blood mononuclear cells were analyzed before and at 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Proportions of APCs were determined by flow cytometry. CD14+ monocytes were further analyzed for the expression of costimulatory and adhesion molecules and for their transendothelial migratory capacity in vitro. In addition, CD14+ monocytes from healthy controls were analyzed for their migratory and spreading capacity. RESULTS Proportions and absolute numbers of monocytes were significantly increased in RA patients treated with CTLA-4Ig. The expression of several adhesion molecules was significantly diminished. In addition, monocytes displayed a significant reduction in their endothelial adhesion and transendothelial migratory capacity upon treatment with CTLA-4Ig. Likewise, isolated monocytes from healthy controls revealed a significant reduction in their migratory and spreading activity after preincubation with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. CONCLUSION We describe direct effects of CTLA-4Ig therapy on phenotype and functional characteristics of monocytes in RA patients that might interfere with the migration of monocytes to the synovial tissue. This additional mechanism of CTLA-4Ig might contribute to the beneficial effects of CTLA-4Ig treatment in RA patients.
Nature Immunology | 2014
Nicole Boucheron; Roland Tschismarov; Lisa Göschl; Mirjam A. Moser; Sabine Lagger; Shinya Sakaguchi; Mircea Winter; Florian Lenz; Dijana Vitko; Florian P. Breitwieser; Lena Müller; Hammad Hassan; Keiryn L. Bennett; Jacques Colinge; Wolfgang Schreiner; Takeshi Egawa; Ichiro Taniuchi; Patrick Matthias; Christian Seiser; Wilfried Ellmeier
Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases 1 and 2 (HDAC1 and HDAC2) as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of major histocompatibility complex (MHC) class II–selected CD4+ helper T cells that expressed CD8-lineage genes such as Cd8a and Cd8b1. HDAC1 and HDAC2–deficient T helper type 0 (TH0) and TH1 cells further upregulated CD8-lineage genes and acquired a CD8+ effector T cell program in a manner dependent on Runx-CBFβ complexes, whereas TH2 cells repressed features of the CD8+ lineage independently of HDAC1 and HDAC2. These results demonstrate that HDAC1 and HDAC2 maintain integrity of the CD4 lineage by repressing Runx-CBFβ complexes that otherwise induce a CD8+ effector T cell–like program in CD4+ T cells.
Arthritis Research & Therapy | 2014
Michael Bonelli; Lisa Göschl; Stephan Blüml; Thomas Karonitsch; Carl-Walter Steiner; Günter Steiner; Josef S Smolen; Clemens Scheinecker
IntroductionSystemic lupus erythematosus (SLE) is a heterogenous autoimmune disease, which can affect different organs. Increased proportions of CD4+CD25-Foxp3+ T cells have been described in SLE patients. The exact role of this cell population in SLE patients still remains unclear. We therefore analyzed this T cell subset in a large cohort of SLE patients with different organ manifestations.MethodsPhenotypic analyses, proportions and absolute cell numbers of CD4+CD25-Foxp3+ T cells were determined by flow cytometry (FACS) in healthy controls (HC) (n = 36) and SLE patients (n = 61) with different organ manifestations. CD4+CD25-Foxp3+ T cells were correlated with clinical data, the immunosuppressive therapy and different disease activity indices. In patients with active glomerulonephritis, CD4+CD25-Foxp3+ T cells were analyzed in urine sediment samples. Time course analyses of CD4+CD25-Foxp3+ T cells were performed in patients with active disease activity before and after treatment with cyclophosphamide and prednisone.ResultsCD4+CD25-Foxp3+ T cells were significantly increased in active SLE patients and the majority expressed Helios. Detailed analysis of this patient cohort revealed increased proportions of CD4+CD25-Foxp3+ T cells in SLE patients with renal involvement. CD4+CD25-Foxp3+ T cells were also detected in urine sediment samples of patients with active glomerulonephritis and correlated with the extent of proteinuria.ConclusionCD4+CD25-Foxp3+ T cells resemble regulatory rather than activated T cells. Comparative analysis of CD4+CD25-Foxp3+ T cells in SLE patients revealed a significant association of this newly described cell population with active nephritis. Therefore CD4+CD25-Foxp3+ T cells might serve as an important tool to recognize and monitor SLE patients with renal involvement.
The FASEB Journal | 2016
Guido A. Gualdoni; Katharina A. Mayer; Lisa Göschl; Nicole Boucheron; Wilfried Ellmeier; Gerhard J. Zlabinger
T cells must tightly regulate their metabolic processes to cope with varying bioenergetic demands depending on their state of differentiation. The metabolic sensor AMPK is activated in states of low energy supply andmodulates cellular metabolism toward a catabolic state. Although this enzyme isknown tobeparticularly active in regulatory T (Treg) cells, its impact on T helper (Th)‐cell differentiation is poorly understood. We investigated the impact of several AMPK activators on Treg‐cell differentiation and found that the direct activator AICAR (5‐aminoimidazole‐4‐carboxamide ribonucleotide), but not the indirect activators metformin and 2‐deoxyglucose, strongly enhanced Treg‐cell induction by specifically enhancing Treg‐cell expansion. Conversely, Th17 generation was impaired by the agent. Further investigation of the metabolic background of our observations revealed that AICAR enhanced both cellular mitochondrogenesis and fatty acid uptake. Consistently, increased Treg induction was entirely reversible on inhibition of fatty acid oxidation, thus confirming the dependence of AICARs effects on metabolic pathways alterations. Translating our findings to an in vivo model, we found that the substance enhanced Treg cell generation on IL‐2 complex–induced immune stimulation. We provide a previously unrecognized insight into the delicate interplay between immune cell function and metabolism and delineate a potential novel strategy for metabolism‐targeting immunotherapy.—Gualdoni, G. A., Mayer, K. A., Göschl, L., Boucheron, N., Ellmeier, W., Zlabinger, G. J. The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation. FASEB J. 30, 3800–3809 (2016) www.fasebj.org
Rheumatology | 2016
Michael Bonelli; Lisa Göschl; Stephan Blüml; Thomas Karonitsch; Kiyoshi Hirahara; Elisabeth Ferner; Carl-Walter Steiner; Günter Steiner; Josef S Smolen; Clemens Scheinecker
OBJECTIVE Abatacept (CTLA-4Ig) blocks CD28-mediated T cell activation by binding to the costimulatory B7 ligands CD80/CD86 on antigen presenting cells. Costimulatory molecules, however, can also be expressed on T cells upon activation. Therefore, the aim of our study was to investigate direct effects of CTLA-4Ig on distinct T cell subsets in RA patients. METHODS Phenotypic and functional analyses of CD4(+) T cells, including CD4(+) FoxP3(+) CD25(+) regulatory T cells (Treg), from RA patients were performed before and during CTLA-4Ig therapy. In addition T cells from healthy volunteers were analysed on in vitro culture with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Apoptotic DNA fragmentation in CD4(+) and CD4(+) FoxP3(+) T cells was measured by TUNEL staining. RESULTS We observed an increase in T cells, including Treg cells, after initiation of CTLA-4Ig therapy, which was linked to a downregulation of activation-associated marker molecules and CD95 on CD4(+) T cells and Treg cells. CTLA-4Ig decreased CD95-mediated cell death in vitro in a dose-dependent manner. Functional analysis of isolated Treg cells from RA patients further revealed a diminished suppression of responder T cell proliferation. This was found to be due to CTLA-4Ig-mediated blocking of CD80 and CD86 on responder T cells that led to a diminished susceptibility for Treg cell suppression. CONCLUSION CTLA-4Ig therapy in RA patients exerts effects beyond the suppression of T cell activation, which has to be taken into account as an additional mechanism of CTLA-4Ig treatment.
Science Signaling | 2015
Philipp Schatzlmaier; Supper; Lisa Göschl; Alexander Zwirzitz; Paul Eckerstorfer; Wilfried Ellmeier; Johannes B. Huppa; Hannes Stockinger
The association of lipid rafts with nuclei during partial cell lysis enables their analysis by flow cytometry. Lipid raft analysis by flow cytometry Lipid rafts are dynamic regions of membranes that are involved in cell signaling but are challenging to study because of their small size and dynamic nature. Schatzlmaier et al. found that lipid raft components became associated with nuclei during lysis of cells as the cells passed through a detergent-containing layer in a gradient. In experiments with lymphocytes, the authors demonstrated that this association enabled the quantitative analysis by flow cytometry of the composition of lipid rafts and of the dynamic association of proteins with these membrane microdomains at single-cell resolution. Lipid rafts, a distinct class of highly dynamic cell membrane microdomains, are integral to cell homeostasis, differentiation, and signaling. However, their quantitative examination is challenging when working with rare cells, developmentally heterogeneous cell populations, or molecules that only associate weakly with lipid rafts. We present a fast biochemical method, which is based on lipid raft components associating with the nucleus upon partial lysis during centrifugation through nonionic detergent. Requiring little starting material or effort, our protocol enabled the multidimensional flow cytometric quantitation of raft-resident proteins with single-cell resolution, thereby assessing the membrane components from a few cells in complex cell populations, as well as their dynamics resulting from cell signaling, differentiation, or genetic mutation.
PLOS ONE | 2014
Roland Tschismarov; Sonja Firner; Cristina Gil-Cruz; Lisa Göschl; Nicole Boucheron; Günter Steiner; Patrick Matthias; Christian Seiser; Burkhard Ludewig; Wilfried Ellmeier
Reversible lysine acetylation plays an important role in the regulation of T cell responses. HDAC1 has been shown to control peripheral T helper cells, however the role of HDAC1 in CD8+ T cell function remains elusive. By using conditional gene targeting approaches, we show that LckCre-mediated deletion of HDAC1 led to reduced numbers of thymocytes as well as peripheral T cells, and to an increased fraction of CD8+CD4– cells within the CD3/TCRβlo population, indicating that HDAC1 is essential for the efficient progression of immature CD8+CD4– cells to the DP stage. Moreover, CD44hi effector CD8+ T cells were enhanced in mice with a T cell-specific deletion of HDAC1 under homeostatic conditions and HDAC1-deficient CD44hi CD8+ T cells produced more IFNγ upon ex vivo PMA/ionomycin stimulation in comparison to wild-type cells. Naïve (CD44l°CD62L+) HDAC1-null CD8+ T cells displayed a normal proliferative response, produced similar amounts of IL-2 and TNFα, slightly enhanced amounts of IFNγ, and their in vivo cytotoxicity was normal in the absence of HDAC1. However, T cell-specific loss of HDAC1 led to a reduced anti-viral CD8+ T cell response upon LCMV infection and impaired expansion of virus-specific CD8+ T cells. Taken together, our data indicate that HDAC1 is required for the efficient generation of thymocytes and peripheral T cells, for proper CD8+ T cell homeostasis and for an efficient in vivo expansion and activation of CD8+ T cells in response to LCMV infection.
Annals of the Rheumatic Diseases | 2012
Michael Bonelli; Lisa Göschl; Stephan Blüml; Josef S Smolen; Clemens Scheinecker
Background Abatacept (CTLA-4Ig) inhibits the binding of CD28 to the B7 ligands CD80/CD86 on antigen presenting cells (APC) and thereby effector T cell activation. Costimulatory molecules can also be expressed on T cells upon activation. Whether this allows CTLA-4Ig to directly affect distinct T cell subsets remains unclear. The authors therefore performed phenotypic and functional analysis of T cells in RA patients before and after CTLA-4Ig therapy. Methods Peripheral blood mononuclear cells (PBMC) from RA patients (n=15) were analysed before, 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Phenotypic analyses on different T cell subsets were performed by FACS. Apoptosis was induced in CTLA-4Ig incubated cells by anti-Fas antibody and DNA fragmentation was measured by TUNEL staining. CD4+CD25+ Treg were isolated from RA patients by cell sorting and analysed for their functional capacity. Suppression assays were performed with Treg and responder T cells from HC after preincubation of individual cell populations with CTLA-4Ig or with antibodies (Abs) against costimulatory B7 molecules. Summary Proportions of CD4+ T cells and Treg substantially increased 2 and 4 weeks after the initiation of CTLA-4Ig treatment. No differences were observed for the percentage of memory and naïve CD4+ T cells. Phenotypic analyses revealed a downregulation of activation associated marker molecules and of CD95 on CD4+ T cells and Treg. Likewise, preincubation of PBMCs from HC with CTLA-4Ig before stimulation led to a dose dependent downregulation of activation markers on CD4 cells and Treg in vitro. Moreover in vitro analyses of CD4+ T cells and Treg from HC showed a dose dependent decrease in AICD after incubation with CTLA-4Ig. Functional analysis of isolated Treg from RA patients revealed a diminished suppressive capacity of Treg 4 weeks after treatment with CTLA-4Ig. However, only the preincubation of responder T cells, but not of Treg, from HC with CTLA-4Ig or with Abs against B7 molecules resulted in a decreased T cell suppression. Conclusion Within our study the authors were able to demonstrate for the first time a direct effect of CTLA-4Ig on T cells in RA patients, which results in increased proportions of CD4+ and Treg, the downregulation of CD95 and a decrease in AICD. Blockade of B7 costimulatory molecules on T cells by CTLA-4Ig leads to a diminished susceptibility of T cells for Treg suppression which might be counter balanced by increased Treg numbers.
Annals of the Rheumatic Diseases | 2011
Michael Bonelli; Lisa Göschl; Stefan Bluml; Eva Rath; Josef S Smolen; Clemens Scheinecker
Objectives Regulatory T cells are critically involved in the pathogenesis of autoimmune diseases. Recently, a novel subset of regulatory T cells has been described in systemic lupus erythematosus (SLE), However, the role of CD4+CD25−Foxp3+ T cells in the pathogenesis of SLE is not known. The authors therefore performed comparative analyses of proportions of CD4+CD25−Foxp3+ T cells in SLE patients with different organ manifestations. Methods Phenotypic analysis of peripheral blood CD4+CD25−Foxp3+ T cells was performed by flow cytometry (FACS) in SLE patients with different organ manifestations and healthy controls (HC). CD4+CD25−Foxp3+ as well as conventional regulatory T cells were analysed for the expression of the recently identified marker Helios and Icos and for their cytokine expression profile and correlated with clinical data, the daily cortisone dose and the SLE disease activity index (SLEDAI). Results The authors report that the proportions of CD4+CD25−Foxp3+ T cells are increased in patients with SLE as compared to HC. Expression of Helios and ICOS in CD4+CD25−Foxp3+ T cells was similar to conventional Tregs, indicating that CD4+CD25−Foxp3+ T cells are bona fide Tregs. Strikingly analysis of patients with different organ manifestations revealed increased proportions of CD4+CD25−Foxp3+ T cells in SLE patients with renal involvement, especially with active glomerulonephritis. Furthermore roportions of CD4+CD25−Foxp3+ T cells correlated with the extent of proteinuria. Ongoing experiments are performed in order to analyse the origin of CD4+CD25−Foxp3+ T cells. Therefore cells are stained for interleukin-4, interleukin-17 and IFN-γ and the transcription factor Foxp3, RORγt and GATA3. Conclusions In summary the authors found increased proportions of CD4+CD25−Foxp3+ T cells in patients with SLE who suffer from glomerulonephritis suggesting their involvement in kidney pathology. CD4+CD25−Foxp3+ T cells might therefore be a useful tool to recognise and monitor patients with renal involvement. Kidney biopsies and a further characterisation of this cell population have been designed to unravel their role in the development of glomerulonephritis in SLE patients.
Journal of Cellular and Molecular Medicine | 2018
Michael Bonelli; Antonia Puchner; Lisa Göschl; Silvia Hayer; Birgit Niederreiter; Guenter Steiner; Katharina Tillmann; Roberto Plasenzotti; Bruno K. Podesser; Philippe Georgel; Josef S Smolen; Clemens Scheinecker; Stephan Blüml
Abstract Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, characterized by synovial infiltration of various inflammatory cells. Chemokines are involved in controlling the recruitment of different cell types into the synovial membrane. The role of CCR6 in the development of arthritis so far remains unclear. In this study, we investigated the role of CCR6 in the pathogenesis of arthritis using three different murine arthritis models. Compared to WT animals, CCR6 −/− mice developed less clinical signs of arthritis in the collagen‐induced arthritis model but not in the K/BxN serum transfer arthritis model and in the human tumour necrosis factor transgenic arthritis model, suggesting a defect in adaptive effector functions but intact innate effector functions in the development of arthritis in CCR6 −/− animals. In line with this, anti‐collagen antibody levels were significantly reduced in CCR6 −/− mice compared with WT mice. Moreover, we demonstrate enhanced osteoclastogenesis in vitro in CCR6 −/− mice compared with WT mice. However, we did not detect differences in bone mass under steady state conditions in vivo between WT and CCR6‐deficient mice. These data suggest that CCR6 is crucially involved in adaptive but not in innate immunity‐driven arthritis. CCR6 or its chemokine ligand CCL20 might represent a possible new target for the treatment of RA.