Institute for Infection Immunology

Hannover, Germany

Institute for Infection Immunology

Hannover, Germany
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Akhmetzyanova I.,University of Duisburg - Essen | Zelinskyy G.,University of Duisburg - Essen | Schimmer S.,University of Duisburg - Essen | Brandau S.,University of Duisburg - Essen | And 3 more authors.
Cancer Immunology, Immunotherapy | Year: 2013

The important role of tumor-specific cytotoxic CD8+ T cells is well defined in the immune control of the tumors, but the role of effector CD4+ T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4 + T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4+ T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8+ T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4+ T cells and increases FV-specific CD4+ T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4+ T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4 + T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors. © 2012 The Author(s).

Pellegrini M.,Walter and Eliza Hall Institute of Medical Research | Pellegrini M.,University of Melbourne | Pellegrini M.,Campbell University | Calzascia T.,Campbell University | And 17 more authors.
Cell | Year: 2011

Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases. © 2011 Elsevier Inc.

Schuster M.,Helmholtz Center for Infection Research | Schuster M.,Otto Von Guericke University of Magdeburg | Glauben R.,Charité - Medical University of Berlin | Plaza-Sirvent C.,Helmholtz Center for Infection Research | And 14 more authors.
Immunity | Year: 2012

Forkhead box P3 positive (Foxp3+) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NFκB (IκB) IκBNS drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκBNS deficiency leads to a substantial reduction of Foxp3+ Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-β (TGF-β) treatment in vitro. Moreover, fewer Foxp3+ Treg cells developed from IκBNS-deficient CD25-CD4+ T cells adoptively transferred into immunodeficient recipients. Importantly, IκBNS was required for the transition of immature GITR+CD25+Foxp3- thymic Treg cell precursors into Foxp3+ cells. In contrast to mice lacking c-Rel or Carma1, IκBNS-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκBNS critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκBNS could modulate the Treg cell compartment. © 2012 Elsevier Inc.

Villalta S.A.,University of California at San Francisco | Rosenthal W.,University of California at San Francisco | Martinez L.,University of California at Los Angeles | Kaur A.,University of California at San Francisco | And 5 more authors.
Science Translational Medicine | Year: 2014

We examined the hypothesis that regulatory T cells (Tregs) modulate muscle injury and inflammation in the mdx mouse model of Duchenne muscular dystrophy (DMD). Although Tregs were largely absent in the muscle of wildtype mice and normal human muscle, they were present in necrotic lesions, displayed an activated phenotype, and showed increased expression of interleukin-10 (IL-10) in dystrophic muscle from mdx mice. Depletion of Tregs exacerbated muscle injury and the severity of muscle inflammation, which was characterized by an enhanced interferon-γ (IFN-γ) response and activation of M1 macrophages. To test the therapeutic value of targeting Tregs in muscular dystrophy, we treated mdx mice with IL-2/anti-IL-2 complexes and found that Tregs and IL-10 concentrations were increased in muscle, resulting in reduced expression of cyclooxygenase-2 and decreased myofiber injury. These findings suggest that Tregs modulate the progression of muscular dystrophy by suppressing type 1 inflammation in muscle associated with muscle fiber injury, and highlight the potential of Treg-modulating agents as therapeutics for DMD.

Teng M.W.L.,Peter MacCallum Cancer Center | Teng M.W.L.,University of Melbourne | Ngiow S.F.,Peter MacCallum Cancer Center | Ngiow S.F.,University of Melbourne | And 5 more authors.
Cancer Research | Year: 2010

Foxp3 is a central control element in the development and function of regulatory T cells (Treg), and mice expressing a diphtheria toxin (DT) receptor - enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus (DEREG mice) allow conditional and efficient depletion of Foxp3+ Treg by DT injection. Herein, we use DEREG mice and a mouse model of carcinogenesis to show that conditional and effective Treg depletion can both protect mice from carcinogenesis by innate control, yet permanently eradicate a proportion of de novo - established tumors in mice in a largely CD8+ T-cell - and IFN-γ - dependent manner. Tumors displayed a heterogeneous response to Treg depletion, and suppression of established tumors was accompanied by an increase in the tumor-infiltrating CD8+ T-cell/B-cell ratio. Tumor rejection occurred in the absence of overt autoimmunity, suggesting that effective transient Treg depletion strategies may be therapeutic in at least a proportion of spontaneous tumors developing in the host. ©2010 AACR.

Engel D.R.,University of Bonn | Koscielny A.,University of Bonn | Wehner S.,University of Bonn | Maurer J.,University of Bonn | And 9 more authors.
Nature Medicine | Year: 2010

Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103 + CD11b + dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ 3 (IFN-γ 3) secretion by CCR9 + memory T helper type 1 (TH1) cells which activates the macrophages. IL-12 also caused some TH1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (T H1-specific T box transcription factor) or IFN-γ 3 prevented postoperative ileus. CCR9 + TH1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a T H 1 immune-mediated disease and identify potential targets for disease monitoring and therapy. © 2010 Nature America, Inc. All rights reserved.

Ghorbani P.,University of Toronto | Ghorbani P.,Institute for Infection Immunology | Santhakumar P.,University of Toronto | Hu Q.,University of Toronto | And 4 more authors.
European Respiratory Journal | Year: 2015

The hypoxic environment of cystic fibrosis airways allows the persistence of facultative anaerobic bacteria, which can produce short-chain fatty acids (SCFAs) through fermentation. However, the relevance of SCFAs in cystic fibrosis lung disease is unknown. We show that SCFAs are present in sputum samples from cystic fibrosis patients in millimolar concentrations (mean±SEM 1.99±0.36 mM). SCFAs positively correlated with sputum neutrophil count and higher SCFAs were predictive for impaired nitric oxide production. We studied the effects of the SCFAs acetate, propionate and butyrate on airway inflammatory responses using epithelial cell lines and primary cell cultures. SCFAs in concentrations present in cystic fibrosis airways (0.5-2.5 mM) affected the release of granulocytemacrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin (IL)-6. SCFAs also resulted in higher IL-8 release from stimulated cystic fibrosis transmembrane conductance regulator (CFTR) F508del-mutant compared to wild-type CFTR-corrected bronchial epithelial cells. At 25 mM propionate reduced IL-8 release in control but not primary cystic fibrosis epithelial cells. Low (0.5-2.5 mM) SCFA concentrations increased, while high (25-50 mM) concentrations decreased inducible nitric oxide synthase expression. In addition, SCFAs affected the growth of Pseudomonas aeruginosa in a concentration- and pH-dependent manner. Thus, our data suggest that SCFAs contribute to cystic fibrosis-specific alterations of responses to airway infection and inflammation. Copyright © ERS 2015.

PubMed | Institute for Infection Immunology, University of Würzburg, Heinrich Heine University Düsseldorf and University of Munster
Type: Journal Article | Journal: PloS one | Year: 2014

Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.

PubMed | Institute for Infection Immunology, Universitatsklinikum Jena, Charité - Medical University of Berlin and University of Würzburg
Type: Journal Article | Journal: European journal of immunology | Year: 2016

Although regulatory T (Treg) cells are necessary to prevent autoimmune diseases, including arthritis, whether Treg cells can ameliorate established inflammatory disease is controversial. Using the glucose-6-phosphate isomerase (G6PI)-induced arthritis model in mice, we aimed to determine the therapeutic efficacy of increasing Treg cell number and function during chronic destructive arthritis. Chronic destructive arthritis was induced by transient depletion of Treg cells prior to immunization with G6PI. At different time points after disease induction, mice were treated with a CD28 superagonistic antibody (CD28SA). CD28SA treatment during the induction phase of arthritis ameliorated the acute signs of arthritis and completely prevented the development of chronic destructive arthritis. CD28SA treatment of mice with fully developed arthritis induced a significant reduction in clinical and histological signs of arthritis. When given during the chronic destructive phase of arthritis, 56 days after disease induction, CD28SA treatment resulted in a modest reduction of clinical signs of arthritis and a reduction in histopathological signs of joint inflammation. Our data show that increasing the number and activation of Treg cells by a CD28SA is therapeutically effective in experimental arthritis.

Re S.L.,Catholic University of Leuven | Lecocq M.,Catholic University of Leuven | Uwambayinema F.,Catholic University of Leuven | Yakoub Y.,Catholic University of Leuven | And 8 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011

Rationale: There is evidence that CD4 + effector T lymphocytes (T eff) participate in the development of lung fibrosis, but the role of their CD4 + regulatory T-cell (T reg) counterparts remains to be determined. Objectives: To elucidate the contribution of T reg cells in a mouse model of lung fibrosis induced by silica (SiO 2) particles. Methods: Lung T reg and T eff cells purified from SiO 2-treated Foxp3- GFP transgenic mice were cocultured with naive lung fibroblasts or transferred to the lungs of healthy mice. DEREG mice, which express the diphtheria toxin receptor under the control of the foxp3 gene, were used to deplete T reg cells during fibrogenesis. Measurements and Main Results: CD4 + Foxp3 + T reg cells were persistently recruited in the lungs in response to SiO 2. T reg accumulation paralleled the establishment of pulmonary immunosuppression and fibrosis. T reg cells highly expressed platelet-derived growth factor (PDGF)-B via a TGF-β autocrine signaling pathway, directly stimulated fibroblast proliferation in vitro, and increased lung collagen deposition upon transfer in the lung of naive mice. The direct profibrotic effects of T reg cells were abolished by the inhibitor of the PDGF-B/TGF-β signaling pathway, imatinib mesylate. Neutralization of T reg-immunosuppressive activity resulted in enhanced accumulation of T eff cells and IL-4-driven pulmonary fibrogenesis, further demonstrating that T reg cells control T eff cell functions during inflammatory fibrosis. Conclusions: Our study indicates that T reg cells contribute to lung fibrosisby stimulating fibroblasts through the secretion of PDGF-B in noninflammatory conditions and regulate detrimental T eff cell activities during inflammation-related fibrosis. Copyright © 2011 by the American Thoracic Society.

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