Institute of Infection Immunology

Hannover, Germany

Institute of Infection Immunology

Hannover, Germany
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Wheeler K.,University of Virginia | Tardif S.,Texas Tech University Health Sciences Center | Rival C.,University of Virginia | Luu B.,University of Virginia | And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2011

Vasectomy is a well accepted global contraceptive approach frequently associated with epididymal granuloma and sperm autoantibody formation. To understand thelong-termsequelae of vasectomy, we investigated the early immune response in vasectomized mice. Vasectomy leads to rapid epithelial cell apoptosis and necrosis, persistent inflammation, and sperm granuloma formation in the epididymis. Vasectomized B6AF1 mice did not mount autoimmune response but instead developed sperm antigen-specific tolerance, documented as resistance to immunization-induced experimental autoimmune orchitis (EAO) but not experimental autoimmune encephalomyelitis. Strikingly, tolerance switches over to pathologic autoimmune state following concomitant CD4+CD25 +Foxp3+ regulatory T cell (Treg) depletion: unilaterally vasectomized mice produce dominant autoantibodies to an orchitogenic antigen (zonadhesin), and develop CD4 T-cell- and antibody-dependent bilateral autoimmune orchitis. Therefore, (i) Treg normally prevents spontaneous organ-specific autoimmunity induction by persistent endogenous danger signal, and (ii) autoantigenic stimulation with sterile autoinflammation can lead to tolerance. Finally, postvasectomy tolerance occurs in B6AF1, C57BL/6, and A/J strains. However, C57BL/6 mice resisted EAO after 60% Treg depletion, but developed EAO after 97% Treg reduction. Therefore, variance in intrinsic Treg function - a possible genetic trait - can influence the divergent tolerogenic versus autoimmune response to vasectomy.

Hadis U.,Hannover Medical School | Wahl B.,Hannover Medical School | Schulz O.,Hannover Medical School | Hardtke-Wolenski M.,Hannover Medical School | And 6 more authors.
Immunity | Year: 2011

Tolerance to food antigen manifests in the absence and/or suppression of antigen-specific immune responses locally in the gut but also systemically, a phenomenon known as oral tolerance. Oral tolerance is thought to originate in the gut-draining lymph nodes, which support the generation of FoxP3+ regulatory T (Treg) cells. Here we use several mouse models to show that Treg cells, after their generation in lymph nodes, need to home to the gut to undergo local expansion to install oral tolerance. Proliferation of Treg cells in the intestine and production of interleukin-10 by gut-resident macrophages was blunted in mice deficient in the chemokine (C-X3-C motif) receptor 1 (CX3CR1). We propose a model of stepwise oral tolerance induction comprising the generation of Treg cells in the gut-draining lymph nodes, followed by migration into the gut and subsequent expansion of Treg cells driven by intestinal macrophages. © 2011 Elsevier Inc.

Boissonnas A.,University Pierre and Marie Curie | Scholer-Dahirel A.,University Pierre and Marie Curie | Simon-Blancal V.,University Pierre and Marie Curie | Pace L.,University Pierre and Marie Curie | And 6 more authors.
Immunity | Year: 2010

Regulatory T (Treg) cells limit the onset of effective antitumor immunity, through yet-ill-defined mechanisms. We showed the rejection of established ovalbumin (OVA)-expressing MCA101 tumors required both the adoptive transfer of OVA-specific CD8+ T cell receptor transgenic T cells (OTI) and the neutralization of Foxp3+ T cells. In tumor-draining lymph nodes, Foxp3+ T cell neutralization induced a marked arrest in the migration of OTI T cells, increased numbers of dendritic cells (DCs), and enhanced OTI T cell priming. Using an in vitro cytotoxic assay and two-photon live microscopy after adoptive transfer of DCs, we demonstrated that Foxp3+ T cells induced the death of DCs in tumor-draining lymph nodes, but not in the absence of tumor. DC death correlated with Foxp3+ T cell-DC contacts, and it was tumor-antigen and perforin dependent. We conclude that Foxp3+ T cell-dependent DC death in tumor-draining lymph nodes limits the onset of CD8+ T cell responses. © 2010 Elsevier Inc. All rights reserved.

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.

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.

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.

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.

Reuter D.,University of Würzburg | Sparwasser T.,Institute of Infection Immunology | Hunig T.,University of Würzburg | Schneider-Schaulies J.,University of Würzburg
PLoS ONE | Year: 2012

We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4 + CD25 + Foxp3 + Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8 + T cells predominantly recognising the H-2D b-presented viral hemagglutinin epitope MV-H 22-30 (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8 + effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS. © 2012 Reuter et al.

Lochner M.,Institute of Infection Immunology
Gut Microbes | Year: 2011

In mammals, a variety of different lymphoid tissues have evolved as an integral part of the immune system that allows the host to survive in a sometimes hostile environment. While the development of secondary lymphoid organs is programmed in the fetus, the induction of other lymphoid structures like isolated lymphoid follicles (ILFs) in the gut or tertiary lymphoid tissues (tLT) need additional external triggers after birth. It is well established that for the development of secondary lymphoid organs, as well as ILFs, RORγt expressing lymphoid tissue inducer (LTi) cells play an important role. Yet, the requirement of these cells for tLT induction, especially in the gut, was less clear. Here, I will discuss recent data demonstrating that RORγt expressing LTi cells are not required for the development of tLT in the colon. In contrast, such structures even develop spontaneously in the absence of RORγt. In RORγt-/- mice, this is part of the host's strategy to establish a viable homeostasis between the intestinal microbiota and the host, despite the loss of important components of the intestinal immune system in these mice. Although this highlights the amazing capacity of the immune system for adaptation, I will also discuss the adverse effects of such a compensatory immune mechanism for the host. © 2011 Landes Bioscience.

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.

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