Time filter

Source Type

Loebbermann J.,Imperial College London | Thornton H.,Imperial College London | Durant L.,Imperial College London | Sparwasser T.,Institute of Infection Immunology | And 5 more authors.
Mucosal Immunology | Year: 2012

The inflammatory response to lung infections must be tightly regulated, enabling pathogen elimination while maintaining crucial gas exchange. Using recently described depletion of regulatory T cell (DEREG) mice, we found that selective depletion of regulatory T cells (Tregs) during acute respiratory syncytial virus (RSV) infection enhanced viral clearance but increased weight loss, local cytokine and chemokine release, and T-cell activation and cellular influx into the lungs. Conversely, inflammation was decreased when Treg numbers and activity were boosted using interleukin-2 immune complexes. Unexpectedly, lung (but not draining lymph node) Tregs from RSV-infected mice expressed granzyme B (GzmB), and bone marrow chimeric mice with selective loss of GzmB in the Treg compartment displayed markedly enhanced cellular infiltration into the lung after infection. A crucial role for GzmB-expressing Tregs has not hitherto been described in the lung or during acute infections, but may explain the inability of children with perforin/GzmB defects to regulate immune responses to infection. The effects of RSV infection in mice with defective immune regulation closely parallel the observed effects of RSV in children with bronchiolitis, suggesting that the pathogenesis of bronchiolitis may involve an inability to regulate virus-induced inflammation. 2012 Society for Mucosal Immunology. Source

Schwarz A.,University of Kiel | Navid F.,University of Kiel | Sparwasser T.,Institute of Infection Immunology | Clausen B.E.,Rotterdam University | Schwarz T.,University of Kiel
Journal of Investigative Dermatology | Year: 2012

Low-dose UV radiation (UVR) inhibits the induction of contact hypersensitivity and induces regulatory T cells (Tregs), which because of their antigen specificity harbor therapeutic potential. Topical application of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3) is known to induce Tregs as well, which implies that 1,25(OH) 2 D 3 might be involved in UVR-induced immunosuppression. It was the aim of this study to clarify this issue, to further characterize 1,25(OH) 2 D 3-induced Tregs and to determine whether they differ from UVR-induced Tregs. Our data demonstrate that 1,25(OH) 2 D 3-induced Tregs act in an antigen-specific manner and belong to the Foxp3-expressing subtype of Tregs as demonstrated by diphtheria toxin (DT)-mediated depletion of Foxp3 + Tregs in DEREG (depletion of Tregs) mice. Using Langerin-DTR (DT receptor) knock-in mice, it was shown that Langerhans cells (LCs) are required for the induction of Tregs by 1,25(OH) 2 D 3, as depletion of LCs but not Langerin + dermal dendritic cells abrogated the induction of Tregs. Taken together, 1,25(OH) 2 D 3 affects the immune system in a similar manner as UVR, probably using the same pathways. However, vitamin D receptor knockout mice were equally susceptible to UVR-induced immunosupppression as wild-type controls. This indicates that 1,25(OH) 2 D 3 exerts similar immunosuppressive effects as UVR but is dispensable for local UVR-induced immunosuppression. © 2012 The Society for Investigative Dermatology. Source

Wang Y.,Cedars Sinai Medical Center | Sparwasser T.,Institute of Infection Immunology | Figlin R.,Cedars Sinai Medical Center | Kim H.L.,Cedars Sinai Medical Center
Cancer Research | Year: 2014

Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3- expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3+ T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3+ T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients. © 2014 American Association for Cancer Research. Source

Schwarz A.,University of Kiel | Navid F.,University of Kiel | Sparwasser T.,Institute of Infection Immunology | Clausen B.E.,Erasmus University Rotterdam | Schwarz T.,University of Kiel
Journal of Allergy and Clinical Immunology | Year: 2011

Background: Regulatory T (Treg) cells induced by UV radiation (UVR) inhibit only the induction and not the elicitation of contact hypersensitivity (CHS) because they migrate into the lymph nodes but not the skin. The tissue-homing receptor expression and migratory behavior of Treg cells can be altered by means of in vitro coincubation with skin-derived antigen-presenting cells. On this in vitro treatment, Treg cells migrate into the skin and thus inhibit the elicitation of CHS. Objective: We attempted to determine whether Treg cells can be induced by UVR in sensitized mice and manipulated entirely in vivo in such a way that they suppress the elicitation of immune responses. Methods: Treg cells were induced by applying contact allergens onto UV-exposed skin in wild-type, langerin diphtheria toxin receptor knock-in, or depletion of Treg cell transgenic mice. Results: UVR-induced Treg cells inhibit the elicitation of CHS in sensitized mice when stimulated by means of an antigen-specific boost through the skin. This requires cutaneous antigen-presenting cells that alter the migratory behavior of Treg cells and drive them out of the lymph nodes into the skin. Conclusions: The indication is that antigen-specific Treg cells can be induced in sensitized hosts and manipulated in such a way that they suppress the elicitation of specific immune reactions. Because this is achieved entirely in vivo without invasive interventions, our findings might have important implications for strategies aiming to induce and use Treg cells in a therapeutic setting. © 2011 American Academy of Allergy, Asthma & Immunology. Source

Berod L.,Institute of Infection Immunology
Nature medicine | Year: 2014

Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases. Source

Discover hidden collaborations