Publications (103) View all
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Article: Maturation of Lymph Node Fibroblastic Reticular Cells from Myofibroblastic Precursors Is Critical for Antiviral Immunity.
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ABSTRACT: The stromal scaffold of the lymph node (LN) paracortex is built by fibroblastic reticular cells (FRCs). Conditional ablation of lymphotoxin-β receptor (LTβR) expression in LN FRCs and their mesenchymal progenitors in developing LNs revealed that LTβR-signaling in these cells was not essential for the formation of LNs. Although T cell zone reticular cells had lost podoplanin expression, they still formed a functional conduit system and showed enhanced expression of myofibroblastic markers. However, essential immune functions of FRCs, including homeostatic chemokine and interleukin-7 expression, were impaired. These changes in T cell zone reticular cell function were associated with increased susceptibility to viral infection. Thus, myofibroblasic FRC precursors are able to generate the basic T cell zone infrastructure, whereas LTβR-dependent maturation of FRCs guarantees full immunocompetence and hence optimal LN function during infection.Immunity 04/2013; · 21.64 Impact Factor -
Article: IκB(NS) Protein Mediates Regulatory T Cell Development via Induction of the Foxp3 Transcription Factor.
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ABSTRACT: 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) IκB(NS) drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκB(NS) 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 IκB(NS)-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, IκB(NS) 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, IκB(NS)-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκB(NS) critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκB(NS) could modulate the Treg cell compartment.Immunity 11/2012; · 21.64 Impact Factor -
Article: Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory.
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ABSTRACT: Although regulatory T cells (T(regs)) are known to suppress self-reactive autoimmune responses, their role during T cell responses to nonself antigens is not well understood. We show that T(regs) play a critical role during the priming of immune responses in mice. T(reg) depletion induced the activation and expansion of a population of low-avidity CD8(+) T cells because of overproduction of CCL-3/4/5 chemokines, which stabilized the interactions between antigen-presenting dendritic cells and low-avidity T cells. In the absence of T(regs), the avidity of the primary immune response was impaired, which resulted in reduced memory to Listeria monocytogenes. These results suggest that T(regs) are important regulators of the homeostasis of CD8(+) T cell priming and play a critical role in the induction of high-avidity primary responses and effective memory.Science 10/2012; 338(6106):532-6. · 31.20 Impact Factor -
Article: Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth.
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ABSTRACT: Infiltration of Foxp3(+) regulatory T (T reg) cells is considered to be a critical step during tumor development and progression. T reg cells supposedly suppress locally an effective anti-tumor immune response within tumor tissues, although the precise mechanism by which T reg cells infiltrate the tumor is still unclear. We provide evidence that Neuropilin 1 (Nrp-1), highly expressed by Foxp3(+) T reg cells, regulates the immunological anti-tumor control by guiding T reg cells into the tumor in response to tumor-derived vascular endothelial growth factor (VEGF). We demonstrate for the first time that T cell-specific ablation of Nrp-1 expression results in a significant breakdown in tumor immune escape in various transplantation models and in a spontaneous, endogenously driven melanoma model associated with strongly reduced tumor growth and prolonged tumor-free survival. Strikingly, numbers of tumor-infiltrating Foxp3(+) T reg cells were significantly reduced accompanied by enhanced activation of CD8(+) T cells within tumors of T cell-specific Nrp-1-deficient mice. This phenotype can be reversed by adoptive transfer of Nrp-1(+) T reg cells from wild-type mice. Thus, our data strongly suggest that Nrp-1 acts as a key mediator of Foxp3(+) T reg cell infiltration into the tumor site resulting in a dampened anti-tumor immune response and enhanced tumor progression.Journal of Experimental Medicine 10/2012; 209(11):2001-16. · 13.85 Impact Factor -
Article: TLR2 Agonist-Allergen Coupling Efficiently Redirects Th2 Cell Responses and Inhibits Allergic Airway Eosinophilia.
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ABSTRACT: Abstract Toll-like receptor (TLR) agonists have been described to beneficially modulate allergic airway inflammation. However, the efficiency of TLR agonists vary considerably and the exact cellular mechanisms, especially of TLR 2/6 agonists, are incompletely understood. We aimed to investigate at a cellular level, if administration of the pharmacologically improved TLR 2/6 agonist BPPcysMPEG (BPP) conjugated to antigenic peptide (BPP-OVA) could divert an existing Th2 response and influence airway eosinophilia. The effects of BPP-OVA on airway inflammation were assessed in a classical murine sensitization/challenge model and an adoptive transfer model, which involved adoptive transfer of in vitro differentiated OVA-specific Th2 cells. Functional T cell stimulation by lung dendritic cells (DC) was determined both, in vitro as well as in vivo combined with cytokine secretion analysis. A single mucosal BPP-OVA application efficiently delivered antigen, led to TLR2-mediated DC activation and resulted in OVA-specific T cell proliferation via lung DC in vivo. In alternative models of allergic airway disease, single administration of BPP-OVA before OVA challenge, but not BPP alone, significantly reduced airway eosinophilia, mostly likely through altered antigen-specific T cell stimulation via DC. Analysis of adoptively transferred Th2-biased cells after BPP-OVA administration in vivo, suggested that BPP-OVA guides antigen-specific Th2- cells to produce significantly higher amount of IFNγ upon allergen challenge. In conclusion, our data show for the first time that, a single mucosal administration of a TLR 2/6 agonist-allergen conjugate can provoke IFNγ-responses in Th2-biased cells and alleviate allergic airway inflammation.American Journal of Respiratory Cell and Molecular Biology 09/2012; · 5.13 Impact Factor
