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Ramirez-Ortiz Z.G.,University of Massachusetts Medical School | Lee C.K.,University of Massachusetts Medical School | Wang J.P.,University of Massachusetts Medical School | Boon L.,Bioceros | And 2 more authors.
Cell Host and Microbe | Year: 2011

While plasmacytoid dendritic cells (pDCs), a natural type I interferon (IFN)-producing cell type, are regarded as critical for innate immunity to viruses, their role in defense against fungal infections remains unknown. We examined the interactions of pDCs with hyphae of the invasive human fungal pathogen Aspergillus fumigatus. Human pDCs spread over hyphae and inhibited their growth. Antifungal activity was retained in pDC lysates, did not require direct fungal contact, and was partially reversed by zinc. Incubation with hyphae resulted in pDC cytotoxicity, partly due to fungal gliotoxin secretion. Following hyphal stimulation, pDCs released proinflammatory cytokines via a TLR9-independent mechanism. Pulmonary challenge of mice with A. fumigatus resulted in a substantial influx of pDCs into lungs, and pDC-depleted mice were hypersusceptible to invasive aspergillosis. These data demonstrate the antifungal activity of pDCs against A. fumigatus and establish their nonredundant role in host defenses against invasive aspergillosis in vivo. © 2011 Elsevier Inc. Source


De Bruin A.M.,University of Amsterdam | Buitenhuis M.,Erasmus Medical Center | Van Der Sluijs K.F.,University of Amsterdam | Van Gisbergen K.P.J.M.,University of Amsterdam | And 2 more authors.
Blood | Year: 2010

To explore whether and how T cells can affect myelopoiesis, we investigated myeloid differentiation in a model for T cell-mediated immune activation. We found that CD70-transgenic (CD70TG) mice, which have elevated numbers of interferon-γ (IFN-γ)-producing effector T cells in the periphery and bone marrow, are almost devoid of eosinophilic granulocytes. Induction of allergic airway inflammation in these mice failed to induce eosinophilia as well as airway hyper-responsiveness. CD70TG mice also have strongly reduced numbers of eosinophil lineage-committed progenitors, whereas granulocyte/macrophage progenitors from these mice are unable to generate eosinophils in vitro.We found that granulocyte/macrophage progenitors express IFN-γR1 and that IFN-γ is sufficient to inhibit eosinophil differentiation of both murine and human progenitor cells in vitro. We demonstrate that inhibition of eosinophil development in CD70TG mice is IFN-γ-dependent and that T cell-derived IFN-γ is sufficient to inhibit eosinophil formation in vivo. Finally, we found that IFN-γ produced on anti-CD40 treatment and during viral infection can also suppress eosinophil formation in wild-type mice. These data demonstrate that IFN-γ inhibits the differentiation of myeloid progenitors to eosinophils, indicating that the adaptive immune system plays an important role in orchestrating the formation of the appropriate type of myeloid cells during immune activation. © 2010 by The American Society of Hematology. Source


Vahl J.C.,Max Planck Institute of Biochemistry | Heger K.,Max Planck Institute of Biochemistry | Knies N.,Max Planck Institute of Biochemistry | Knies N.,TU Munich | And 5 more authors.
PLoS Biology | Year: 2013

Natural killer T (NKT) cell development depends on recognition of self-glycolipids via their semi-invariant Vα14i-TCR. However, to what extent TCR-mediated signals determine identity and function of mature NKT cells remains incompletely understood. To address this issue, we developed a mouse strain allowing conditional Vα14i-TCR expression from within the endogenous Tcrα locus. We demonstrate that naïve T cells are activated upon replacement of their endogenous TCR repertoire with Vα14i-restricted TCRs, but they do not differentiate into NKT cells. On the other hand, induced TCR ablation on mature NKT cells did not affect their lineage identity, homeostasis, or innate rapid cytokine secretion abilities. We therefore propose that peripheral NKT cells become unresponsive to and thus are independent of their autoreactive TCR. © 2013 Vahl et al. Source


Mus A.M.C.,Erasmus Medical Center | Cornelissen F.,Erasmus Medical Center | Asmawidjaja P.S.,Erasmus Medical Center | Van Hamburg J.P.,Erasmus Medical Center | And 3 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. To examine the role of interleukin-23 (IL-23) in subgroup polarization of IL-17A-positive and/or interferon-γ (IFNγ)-positive T cells in autoimmune disease-prone DBA/1 mice with and without collagen-induced arthritis. Methods. A magnetic-activated cell sorting system was used to isolate CD4+ T cells from the spleen of naive and type II collagen (CII)-immunized DBA/1 mice. These CD4+ T cells were stimulated in vitro under Th0, Th1, or different Th17 culture conditions. Intracellular staining for IL-17A and IFNγ was evaluated by flow cytometry. In addition, Th17 cytokines and T helper-specific transcription factors were analyzed by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. Results. In CD4+ T cells from naive DBA/1 mice, IL-23 alone hardly induced retinoic acid-related orphan receptor γt (RORγt), Th17 polarization, and Th17 cytokines, but it inhibited T-bet expression. In contrast, transforming growth factor β1 (TGFβ1)/IL-6 was a potent inducer of RORγt, RORα, IL-17A, IL-17F, IL-21, and FoxP3 in these cells. In contrast to TGFβ1/IL-6, IL-23 was critical for the induction of IL-22 in CD4+ T cells from both naive and CII-immunized DBA/1 mice. Consistent with these findings, IL-23 showed a more pronounced induction of the IL-17A+IFNγ- subset in CD4+ T cells from CII-immunized mice. However, in CD4+ T cells from naive mice, IL-23 significantly increased the TGFβ1/IL-6-induced Th17 polarization, including elevated levels of IL-17A and IL-17F and decreased expression of T-bet and FoxP3. Of note, the IL-23-induced increase in IL-17A and IL-17F levels was prevented in T-bet-deficient mice. Conclusion. IL-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of IL-22, but not IL-21, levels in autoimmune arthritis. These data indicate different mechanisms for IL-23 and TGFβ1/IL-6 at the transcription factor level during Th17 differentiation in autoimmune experimental arthritis. © 2010, American College of Rheumatology. Source


Kamburova E.G.,Radboud University Nijmegen | Koenen H.J.P.M.,Radboud University Nijmegen | Boon L.,Bioceros | Hilbrands L.B.,Radboud University Nijmegen | Joosten I.,Radboud University Nijmegen
American Journal of Transplantation | Year: 2012

Rituximab is a chimeric anti-CD20 monoclonal antibody (mAb) used in B-cell malignancies, various autoimmune disorders and organ transplantation. Although administration of a single dose of rituximab results in full B-cell depletion in peripheral blood, there remains a residual B-cell population in secondary lymphoid organs. These nondepleted B cells might be altered by exposure to rituximab with subsequent immunomodulatory effects. Therefore, we analyzed in vitro the effects of rituximab on proliferation, activation and differentiation of CD19 + B cells by means of carboxyfluorescein succinimidyl ester (CFSE)-based multiparameter flow cytometry. Rituximab inhibited the proliferation of CD27 - naïve, but not of CD27 + memory B cells. Interestingly, upon stimulation with anti-CD40 mAb and interleukin-21 in the presence of rituximab there was an enrichment of B cells that underwent only one or two cell divisions and displayed an activated naïve phenotype (CD27 -IgD +CD38 -/+). The potency of prestimulated B cells to induce T-cell proliferation was increased by exposure of the B cells to rituximab. Of note, after stimulation with rituximab-treated B cells, proliferated T cells displayed a more Th2-like phenotype. Overall, these results demonstrate that rituximab can affect human B-cell phenotype and function, resulting in an altered outcome of B-T cell interaction. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons. Source

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