Cellule dendritique

Résumé

Les cellules dendritiques sont des cellules du système immunitaire présentes au niveau des muqueuses, et qui sont donc parmi les premières cellules exposées à l'environnement extérieur. Elles sont présentes dans l'épiderme (où elles sont appelées cellules de Langerhans), dans les poumons, et dans l'intestin. Elles résident dans les tissus à l’état immature, et ont une morphologie très variée, qui présentent dans certaines conditions, comme leur nom l'indique, des dendrites (des prolongements cytoplasmiques). Les cellules dendritiques jouent un rôle essentiel dans la présentation antigénique et l'activation de l'immunité adaptative. Elles font partie du système phagocytaire mononucléaire, cellules présentatrices d'antigènes. Les cellules dendritiques ont deux fonctions principales :

le déclenchement de la réponse immunitaire adaptative, dont les acteurs principaux sont les lymphocytes T et les lymphocytes B, dirigée contre des antigènes du « non-soi » ;
le maintien de la toléran

Source officielle

https://fr.wikipedia.org/wiki/Cellule_dendritique

À propos de ce résultat

Cette page est générée automatiquement et peut contenir des informations qui ne sont pas correctes, complètes, à jour ou pertinentes par rapport à votre recherche. Il en va de même pour toutes les autres pages de ce site. Veillez à vérifier les informations auprès des sources officielles de l'EPFL.

Publications associées (100)

Publications associées

Chargement

Personnes associées (28)

Personnes associées

Chargement

Unités associées (10)

Unités associées

Chargement

Concepts associés (85)

Concepts associés

Chargement

Cours associés (15)

Cours associés

Chargement

Séances de cours associées (58)

Séances de cours associées

Chargement

Activin-A, a transforming growth factor êµ family member, is a pleiotropic cytokine with diverse functions in development, fertility, adult tissue homeostasis, and aging. Accordingly, deregulation of Activin-A signaling has been associated with many pathological conditions, including cancer and cancer-associated muscle wasting (cachexia). Activin-A was shown to signal in endocrine, but also local autocrine and paracrine manner. Its secretion in many cancer types is associated with a poor prognosis. Previous studies suggest that Activin-A expression in melanoma promotes tumor growth and metastasis indirectly by inhibiting adaptive anti-tumor immunity, leading to a decrease in the intratumoral frequency of cytotoxic CD8+ T cells (CTLs). However, the underlying mechanisms and the relevant direct target cells of Activin-A and their significance for cancer therapies remained unknown. Similar to other TGFêµ-related ligands, proActivin-A is cleaved by proprotein convertases (PCs) to release mature ligands. However, unlike other family members whose signaling is tightly regulated, Activin-A apparently does not have latency.In this thesis, I characterize proActivin-A cleavage and show that one prodomain can be cleaved independently of known PCs. The resulting hemi-cleaved Activin-A can bind activin type II receptors and induce SMAD3 signaling in reporter cells. A protein interactome screen and analysis of cleavage intermediates in plasma revealed that the hemi-cleaved Activin-A likely interacts with extracellular matrix proteins via the remaining prodomain where it promotes local signaling and regulates trafficking. Luciferase reporter assay showed that hemi-cleaved Activin-A can avoid, at least partially, inhibition by endogenous inhibitors FSTL3 and FST, and enable parallel activation of BMP and Activin signaling pathways. Finally, analysis of B16-F1 melanoma models revealed that only fully cleaved Activin-A in source cells increased tumor growth by acting locally in the tumor microenvironment suggesting that the context of Activin-A precursor processing regulates its tumor growth-promoting effect.The second part of this thesis addresses the mechanisms of Activin-induced immunosuppression in melanoma. We found that Activin-A impairs CTL function indirectly and independently of CD4+ T cell, CSF1R+ macrophages, and IL4 signaling. At least in part, anti-tumor CTL responses are impaired by the inhibitory effects of Activin-A on the secretion of critical CTL-recruiting chemokines CXCL9 and CXCL10 by macrophages and dendritic cells (DCs). Furthermore, Activin-A conferred resistance to immune checkpoint blockade therapy. Characterization of Activin-induced changes in the gene expression of tumor-infiltrating cells by Single cell RNA sequencing revealed that INHBA expression induced the most changes in DCs and least in T cells. Interestingly, the most prominently induced hallmark in Activin-secreting tumors across cell types was the IFN signature. In vitro analyses showed that Activin-A increases IFNÎ³-induced activation of STAT1 and confers resistance to cytostatic IFN signaling in cancer cells.Altogether, the findings of this thesis expand our knowledge on the regulation of Activin-A signaling by precursor cleavage and offer insights into mechanisms of Activin-induced immunosuppression in melanoma. Inhibition of Activin-A maturation thus emerges as a potential new strategy to improve responses to immunotherapies in melanoma and likely other cancers

EPFL2022

Chargement

Modulation of Dendritic Cells Function by H. polygyrus Products

Blaise Dayer

Dendritic cells (DCs) are crucial antigen-presenting cells that can drastically change the development of an immune response by polarising T helper cells toward a Th1 or a Th2 phenotype. Heligmosomoides polygyrus, a murine model of human helminth, has been shown to strongly down-regulate its host immune response. At the DC level, its excretory/secretory products (HES) modulate the cytokine response and co-stimulatory marker expression to bacterial stimulation in favour of an antiinflammatory environment. A regulatory T cell-inducing TGF[beta]-like activity was also discovered in HES. In this work, we further characterised the immunomodulatory properties of HES and heat-inactivated HES both in vitro, using LPS-pulsed GM-CSF-grown bone marrowderived DCs, and in in vivo adoptive transfer of HES-, bacterial extract- or co-pulsed DCs. To determine if the TGF[beta], C-type lectin receptors (CLRs) or toll-like receptors (TLRs) were implicated in this immunomodulation, we treated DCs with blocking antibodies, chemical kinase inhibitors and grew DCs from knockout mice. These studies revealed that HES immunomodulation of DCs was independent of the TGF[beta] receptor, the two CLRs, Dectin-1 and 2, as well as any TLR. Spleen tyrosine kinase (Syk), which is crucial for the signalling of many CLRs, and phosphoinositide 3- kinase seemed not to be needed as well. In an attempt to reduce the number of potential immunomodulators in HES, HES size fractions were tested for their ability to reduce LPS-induced inflammatory cytokine production of DCs. The activity was limited to few fractions, fraction 14 being the most potent. Finally, physical interactions between DCs and biotinylated HES were measured by flow cytometry and revealed that CD24, a molecule required for HES interactions with B cells, was implicated, but not crucial. HES binding to CD24-/- DCs was reduced, but the LPS-induced cytokines and co-stimulatory markers levels were still down-regulated upon HES co-treatment.

2011

Chargement

Dendritic cell chemotaxis in 3D

Ulrike Haessler

Dendritic cells (DCs) are crucial for the onset of adaptive immunity. Their outstanding migratory capacities in combination with their antigen presenting properties make them perfectly suited to pick up antigens in the periphery and transport them to the lymph nodes, where antigen presentation to T-cells is most efficient [1]. Their migration from the periphery to the lymph nodes, called DCs cell homing, is involved in both mounting effective adaptive immune responses as well as maintaining tolerance to self-antigens [2]. Both of them need to be balanced to maintain a healthy organism. So far two alternative mechanisms have been proposed to guide DCs from the interstitium through the extracellular matrix to the proximal lymphatic vessel [3]. One of these mechanisms is based on paracrine chemotaxis towards a CCL21 gradient created by the proximal lymphatic vessel. The second mechanism, called autologous chemotaxis, describes how cells can follow an autocrine gradient, created by the biasing of self-secreted chemokine by interstitial flow [4, 5]. To answer the question of how these two mechanisms contribute to DC homing, a quantitative understanding of how cells respond to gradients and interstitial flow present in their physiological microenvironment is needed [6]. To date, appropriate tools to study DC migration under defined gradients and in the presence of tunable interstitial flow rates in a 3D environment have been lacking. Within this thesis, we present two micro-scale devices that allow live cell observation on an inverted microscope. The first was optimized to expose cells to a steady-state chemokine gradient within a 3D microenvironment and is based on a microfluidic agarose scaffold which functions as a gradient buffer (Chapter 3). The novelty of a gradient buffer allows us to quickly establish stable gradients, which is an important feature in order to create stable and precisely defined gradients during tracking of fast-moving cells like DCs. We then performed an in-depth study of DC cell chemotactic responses towards the CCR7 ligands (CCL19 and CCL21) in 3D using this new agarose chamber (Chapter 4). With the help of an integrated computational model, we could precisely predict the gradient formation of matrix-bound CCL21 versus soluble CCL19 in the microcellular environment and found that DC answer differently to the two chemokines in response to gradient steepness. Furthermore, CCL21 was more chemoattractive than CCL19 when cells were exposed to competing gradients of both chemokines, and this was independent of the CCL21-binding properties. This represents the first quantitative study of CCR7-mediated DC chemotaxis in 3D in response to well-defined ligand gradients. The second device we developed for studying the effects of the physiological flow environment, which cells experience in capillary-fed tissues, on cell migration [6]. A 2-gel strategy allowed us to flexibly fine tune interstitial flow velocities and to precisely determine the actual flow rate for each position imaged on a microscope. We exposed DCs to a wide range of flow rates and observed an increase in persistence under flow compared to static (Chapter 6). In conclusion, this work presents quantitative insights into DC migration within precisely controlled 3D-microenvironments using new devices. It also highlights the role of a quantitative understanding of biological processes to distinguish between chemotactic mechanisms of DC cells.

EPFL2010

Chargement

EPFL2022

Dendritic cell chemotaxis in 3D

Ulrike Haessler

EPFL2010

Modulation of Dendritic Cells Function by H. polygyrus Products

Blaise Dayer

2011