Biomedical subjects

Thibaut De Smedt

Publications and source records attributed to Thibaut De Smedt.

7 recordsLinked to original sources

PubMed2005

Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice.

The cytokine thymic stromal lymphopoietin (TSLP) has been linked to human allergic inflammatory diseases. We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor-deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T helper type 2 cytokines and increased immunoglobulin E. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating bone marrow-derived dendritic cells to upregulate costimulatory molecules and produce the T helper type 2 cell-attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation.

Allergens↗

PubMed2005

Dendritic cell function in mice lacking Plexin C1.

Semaphorins are secreted or transmembrane proteins that provide essential repulsive guidance cues to growing axons or endothelial cells through their receptors of the Plexin and Neuropilin family. Semaphorins and Plexins are also expressed in the immune system where their function remains elusive. In particular, Plexin C1 is expressed by mouse dendritic cells (DCs) and is the receptor for the poxvirus semaphorin homolog A39R. We previously found that Plexin C1 engagement by A39R inhibits integrin-mediated DC adhesion and chemokine-induced migration. Here, we show that a cellular ligand for Plexin C1 is expressed both by activated T cells and DCs, suggesting that Plexin C1 might be engaged on DCs both in cis and in trans. We used Plexin C1(-/-) mice to explore the role of Plexin C1 in DC function. DC development is unaffected in these mice. In two different in vivo assays, Plexin C1(-/-) DC migration to lymph nodes (LNs) was lower than that of wild-type (WT) DC but this difference was not statistically significant. Plexin C1(-/-) bone marrow-derived DCs induced normal in vitro T cell responses but reduced in vivo T cell responses when injected subcutaneously to WT mice. Finally, in vivo T cell responses to ovalbumin peptide and contact hypersensitivity to dinitrofluorobenzene were slightly decreased in Plexin C1(-/-) mice. These results suggest a role for Plexin C1 in DC migration or mobility within the LNs.

Animals↗

PubMed2005

Plexin C1 engagement on mouse dendritic cells by viral semaphorin A39R induces actin cytoskeleton rearrangement and inhibits integrin-mediated adhesion and chemokine-induced migration.

The poxvirus A39R protein is a member of the semaphorin family previously reported to bind plexin C1. We show that, in the mouse, plexin C1 is expressed on dendritic cells (DCs) and neutrophils and is the only receptor for A39R on these cells. The biological effects of a recombinant form of A39R were examined in vitro on mouse DCs derived from wild-type or plexin C1(-/-) mice. A39R binding to plexin C1 on DCs inhibited integrin-mediated adhesion and spreading in vitro. This phenomenon was accompanied by a decrease in integrin signaling, measured by focal adhesion kinase phosphorylation, and a rearrangement of the actin cytoskeleton, without inducing DC maturation or affecting their viability. The A39R effect on DC adhesion was blocked by a specific inhibitor of cofilin phosphorylation, suggesting that the regulation of F-actin turnover by plexin C1 was essential to induce cellular retraction. Furthermore, A39R binding to plexin C1 inhibited chemokine-induced migration of DCs in vitro, suggesting that plexins and semaphorins could be involved in the regulation of leukocyte movement.

Actin Depolymerizing Factors↗

PubMed2005

Poxvirus semaphorin A39R inhibits phagocytosis by dendritic cells and neutrophils.

The poxvirus A39R protein is a member of the semaphorin family that binds to Plexin C1, a molecule expressed on neutrophils and dendritic cells (DC). We previously showed that binding of A39R to Plexin C1 induces local rearrangement of the actin cytoskeleton and inhibits integrin-mediated adhesion, leading to cell retraction. As phagocytosis is dependent on both cytoskeleton integrity and integrin function, we tested the effect of A39R on DC and neutrophil phagocytosis. We found that A39R treatment strongly inhibits phagocytosis by DC and neutrophils in vitro in a Plexin C1-dependent fashion. Moreover, A39R treatment inhibited the capacity of CD8alpha+ DC to take up apoptotic bodies in vivo. As a consequence, A39R impaired the ability of CD8alpha+ DC to cross-prime CD8+ T cells ex vivo. In contrast, A39R had no effect on direct priming of CD8+ T cells by peptide-pulsed CD8alpha+ DC in vitro. These results suggest that poxviruses may use semaphorin homologs as a means to evade the immune system.

Animals↗

PubMed2005

No defect in T-cell priming, secondary response, or tolerance induction in response to inhaled antigens in Fms-like tyrosine kinase 3 ligand-deficient mice.

BACKGROUND: Respiratory tract dendritic cells (DCs) are crucial for the regulation of immune responses to inhaled antigens. However, the precise function of the multiple DC subsets present in the lungs and the lung-draining lymph nodes is unknown. Fms-like tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that drives the development of multiple subsets of DCs in the lymphoid organs. OBJECTIVE: We sought to study the contribution of DC subsets in the regulation of the balance between tolerance and immunity against respiratory antigens by using FLT3L knockout mice. METHODS: Phenotypic analysis of DC subsets in the airways and lungs of FLT3L knockout mice was performed. By using various experimental models, the role of FLT3L-dependent DCs in the priming of naive T cells, the presentation of inhaled antigen to previously primed T H 2 cells, and intranasal tolerance induction was addressed. RESULTS: FLT3L knockout mice display a 90% reduction in lung parenchyma DCs but a normal number of airway DCs and blood monocytes. FLT3L knockout mice had a normal induction of eosinophilic inflammation in response to intranasal administration of allergen. FLT3L-dependent DCs were not required for the presentation of inhaled antigen to previously primed T H 2 cells, and normal induction of T-cell tolerance in response to inhaled antigen was observed in FLT3L knockout mice. CONCLUSION: Airway DC development is independent of FLT3L. FLT3L-dependent DCs are not required for the development and maintenance of airway inflammation or for the induction of intranasal tolerance. Our results point to airway DCs as the major regulators of the balance between tolerance and immunity to inhaled antigens.

Administration, Inhalation↗

PubMed2002

Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs.

The putative counterparts of human plasmacytoid pre-dendritic cells (pDCs) have been described in vivo in mouse models and very recently in an in vitro culture system. In this study, we report that large numbers of bone marrow-derived murine CD11c(+)B220(+) pDCs can be generated with Flt3 ligand (FL) as the sole exogenous differentiation/growth factor and that pDC generation is regulated in vivo by FL because FL-deficient mice showed a major reduction in splenic pDC numbers. We extensively analyzed bone marrow-derived CD11c(+)B220(+) pDCs and described their immature APC phenotype based on MHC class II, activation markers, and chemokine receptor level of expression. CD11c(+)B220(+) pDCs showed a nonoverlapping Toll-like receptor pattern of expression distinct from that of classical CD11c(+)B220(-) dendritic cells and were poor T cell stimulators. Stimulation of CD11c(+)B220(+) pDCs with oligodeoxynucleotides containing certain CpG motifs plus CD40 ligand plus GM-CSF led to increased MHC class II, CD80, CD86, and CD8alpha expression levels, to a switch in chemokine receptor expression that affected their migration, to IFN-alpha and IL-12 secretion, and to the acquisition of priming capacities for both CD4(+) and CD8(+) OVA-specific TCR-transgenic naive T cells. Thus, the in vitro generation of murine pDCs may serve as a useful tool to further investigate pDC biology as well as the potential role of these cells in viral immunity and other settings.

Animals↗

PubMed2002

Ox40 costimulation enhances the development of T cell responses induced by dendritic cells in vivo.

Dendritic cells (DCs) are bone marrow-derived APCs that display unique properties aimed at stimulating naive T cells. Several members of the TNF/TNFR families have been implicated in T cell functions. In this study, we examined the role that Ox40 costimulation might play on the ability of DCs to regulate CD4(+) and CD8(+) T cell responses in vivo. Administration of anti-mouse Ox40 mAb enhanced the Th response induced by immunization with Ag-pulsed DCs, and introduced a bias toward a Th1 immune response. However, anti-Ox40 treatment enhanced the production of Th2 cytokines in IFN-gamma(-/-) mice after immunization with Ag-pulsed DCs, suggesting that the production of IFN-gamma during the immune response could interfere with the development of Th2 lymphocytes induced by DCs. Coadministration of anti-Ox40 with DCs during Ag rechallenge enhanced both Th1 and Th2 responses induced during a primary immunization with DCs, and did not reverse an existing Th2 response. This suggests that Ox40 costimulation amplifies an ongoing immune response, regardless of Th differentiation potential. In an OVA-TCR class II-restricted adoptive transfer system, anti-Ox40 treatment greatly enhanced the level of cytokine secretion per Ag-specific CD4(+) T cell induced by immunization with DCs. In an OVA-TCR class I-restricted adoptive transfer system, administration of anti-Ox40 strongly enhanced expansion, IFN-gamma secretion, and cytotoxic activity of Ag-specific CD8(+) T cells induced by immunization with DCs. Thus, by enhancing immune responses induced by DCs in vivo, the Ox40 pathway might be a target for immune intervention in therapeutic settings that use DCs as Ag-delivery vehicles.

Adjuvants, Immunologic↗