Etude de l'interaction entre les mastocytes et les lymphocytes T helper

Les mastocytes ont longtemps été associés aux réponses allergiques, néanmoins de nombreuses études les décrivent comme des acteurs de la réponse inflammatoire. Les mastocytes sont souvent retrouvés en étroite apposition au sein des tissus avec les lymphocytes T Helper (TH). L'objet de ma thèse est de caractériser la nature de l'interaction mastocyte/TH et notamment la capacité des mastocytes à jouer le rôle de cellules présentatrices d'antigène. Dans une première étude, nous avons démontré que des lignées primaires de mastocytes murins (PCMC) peuvent acquérir un phénotype de cellules présentatrices d'antigènes, lorsqu'elles sont traitées en présence d'IFN-gamma pendant 72 heures. Ainsi conditionnés, les PCMC capturent, apprêtent et présentent l'antigène à des lymphocytes T CD4+ activés, mais restent incapables d'activer leurs homologues naïfs. Durant ce phénomène, une véritable synapse immunologique est mise en place où le lymphocyte TH polarise son TCR et toute sa machinerie sécrétoire vers l'aire de contact intercellulaire. En retour, le mastocyte s'active et baisse significativement le seuil d'activation des récepteurs FcepsilonRI en réponse à une stimulation par des IgE. Ces résultats indiquent que les mastocytes peuvent établir une coopération spécifique avec les lymphocytes TH. Dans une seconde étude, nous avons déterminé les conséquences fonctionnelles d'une telle coopération sur la biologie des lymphocytes TH humains. In vitro les mastocytes humains forment des synapses immunologiques fonctionnelles avec des lymphocytes T CD4+ activés. Ces interactions productives favorisent la génération de lymphocytes TH produisant de grandes quantités d'IL-22 (à la fois de purs TH22 et des TH produisant simultanément de l'IL-22 et de l'IFN-gamma) à partir d'un pool de lymphocytes TH mémoires. Cette différenciation vers un tel profil de TH est dépendante de l'action de deux cytokines que sont l'IL-6 et le TNF-alpha. L'analyse microscopique détaillée d'échantillons de peaux psoriasiques révèle un enrichissement en lymphocytes TH produisant simultanément de l'IL-22 et de l'IFN-gamma, lors qu'ils sont au contact des mastocytes. Ces résultats indiquent que les mastocytes peuvent être de véritables partenaires fonctionnels pour les lymphocytes TH au sein des tissus, leur fournissant des signaux d'activation et les orientant vers la production d'une cytokine supplémentaire l'IL-22.Mast cells have been classically associated to allergic disorders, however several studies describe their involvement in the inflammatory response. Mast cells are often observed in tissues in close apposition with CD4 T cells (TH). The aim of my thesis is to better characterize the nature of mast cell/TH interaction and in particular the mast cell capacity to act as antigen presenting cell and the consequences for the TH cell response. We first addressed this question using mouse primary mast cell lines derived from peritoneal progenitors (PCMC) used as antigen presenting cell to activate cognate OTii T cells with OVA peptide. Our results show that in vitro treatment of PCMC with IFN-gamma and IL-4 induced surface expression of mature MHC class II and costimulatory molecules. When IFN-gamma primed PCMC were used as antigen presenting cells for Helper T (TH) cells, they induced activation of effector T cells but not of their naive counterparts. Confocal laser scanning microscopy showed that TH cells formed immunological synapses and polarized their secretory machinery towards antigen-loaded PCMC. Finally, upon cognate interaction with TH cells, mast cells lowered their threshold of activation via FcepsilonRI. These results show that mast cells can specifically cooperate with class II restricted TH cells. In a second part, we investigated the functional impact of mast cell antigen presentation on human T cell-mediated responses. In vitro, human mast cells form productive immunological synapses with antigen-experienced TH cells. These interactions promote the generation of interleukin 22 (IL-22) producing TH cells (either pure TH22 or IL-22 plus IFN-gamma-producing TH cells) from the circulating CD4+ memory T cell pool via a tumor necrosis factor (TNF-alpha) - and IL-6-dependent mechanism. Three-color immunohistochemistry and confocal laser scanning microscopy reveal a rich infiltrate of IL-22+ TH cells in psoriatic skin biopsies. Most of the IL-22+ TH cells are found in contact with mast cells and co-express IFN-gamma, suggesting that IFN-gamma+IL-22+ TH cells are generated in vivo upon interaction with mast cells. Our results reveal a novel functional trait of mast cells by showing that they can shape the inflammatory potential of human TH lymphocytes in tissues, by providing activating signals and skewing the TH cell response toward the production of IL-22

III-N optoelectronic devices: understanding the physics of electro-optical degradation

III-N optoelectronic devices are of great interest for many applications. Visible emitters (based on InGaN) are widely used in the lighting, display and automotive fields. Ultraviolet LEDs (based on AlGaN) are expected to be widely used for disinfection, medical treatments, surface curing and sensing. Photodetectors and solar cells based on InGaN are also of interest, thanks to their great robustness and wavelength tunability. III-N semiconductors are expected to be robust, thanks to the wide bandgap (allowing high temperature operation) and to the high breakdown field (favoring the robustness against electrostatic discharges and electrical overstress). However, InGaN- and AlGaN-based devices can show a significant degradation when submitted to long-term ageing. Several driving forces can contribute to the worsening of the electrical and optical characteristics, including the operating temperature, the current, and the rate of non-radiative recombination in the quantum wells. The goal of this paper is to discuss the physics of degradation of III-V devices, by presenting a set of recent case studies, evaluated in our laboratories

Deep defects in InGaN LEDs: modeling the impact on the electrical characteristics

Deep defects have a fundamental role in determining the electro-optical characteristics and in the efficiency of InGaN light-emitting diodes (LEDs). However, modeling their effect on the electrical characteristics of the LED is not straightforward. In this paper we analyze the impact of the defects on the electrical characteristics of LEDs: we analyze three single-quantum-well (SQW) InGaN/GaN LED wafers, which differ in the density of defects. Through steady-state photocapacitance (SSPC) and light-capacitance-voltage measurements, the energy levels of these deep defects and their concentrations have been estimated. By means of a simulation campaign, we show that these defects have a fundamental impact on the current voltage characteristic of LEDs, especially in the sub turn-on region. The model adopted takes into consideration trap assisted tunneling as the main mechanism responsible for current leakage in forward bias. For the first time, we use in simulations the defect parameters (concentration, energy) extracted from SSPC. In this way, we can reproduce with great accuracy the current-voltage characteristics of InGaN LEDs in a wide current range (from pA to mA). In addition, based on SSPC measurements, we demonstrate that the defect density in the active region scales with the QW thickness. This supports the hypothesis that defects are incorporated in In-containing layers, consistently with recent publications

Defects in III-N LEDs: experimental identification and impact on electro-optical characteristics

III-N light-emitting-diodes (LEDs) are subject of intense investigations, thanks to their high efficiency and great reliability. The quality of the semiconductor material has a significant impact on the electro-optical performance of LEDs: for this reason, a detailed characterization of defect properties and the modeling of the impact of defects on device performance are of fundamental importance. This presentation addresses this issue, by discussing a set of recent case studies on the topic; specifically, we focus on the experimental characterization of defects, and on the modeling of their impact on the electro-optical characteristics of the devices

Mas-related G protein-coupled receptors (Mrgprs) – Key regulators of neuroimmune interactions

International audienceInterplay between physiological systems in the body plays a prominent role in health and disease. At the cellular level, such interplay is orchestrated through the binding of specific ligands to their receptors expressed on cell surface. G protein-coupled receptors (GPCR) are seven-transmembrane domain receptors that initiate various cellular responses and regulate homeostasis. In this review, we focus on particular GPCRs named Mas-related G protein-coupled receptors (Mrgprs) mainly expressed by sensory neurons and specialized immune cells. We describe the different subfamilies of Mrgprs and their specific ligands, as well as recent advances in the field that illustrate the role played by these receptors in neuro-immune biological processes, including itch, pain and inflammation in diverse organs

Human mast cells as antigen-presenting cells: When is this role important in vivo?

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Étude de l'interaction entre les mastocytes et les lymphocytes T helper

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF