Les cellules dendritiques mérocytiques : un nouveau sous-type de cellules dendritiques conventionnelles spécifiquement régulée par Bim

À l’inverse des autres sous types de cellules dendritiques conventionnelles (cDC), la présentation de peptides dérivés de corps apoptotiques par les DC mérocytiques (mcDC) cause un bris de la tolérance. Ces cellules induisent le diabète lorsqu’elles présentent des peptides dérivés de cellules bêta du pancréas. De plus, chargées avec des peptides dérivés de cellules tumorales, elles permettent la réactivation des lymphocytes T et l’élimination de la tumeur. Ces propriétés spécifiques aux mcDCs mettent en évidence de nouveaux aspects dans le contrôle des bris de tolérance. Comprendre leur relation avec les autres DCs et leur régulation sont nécessaires pour comprendre les mécanismes associés à la tolérance immune. Nous avons déterminé que les mcDCs étaient des cDCs. Les mcDCs sont des cellules avec une courte durée de vie et qui induisent une réponse allogénique. Elles expriment le facteur de transcription spécifique aux cDCs, Zbtb46. Les mcDCs se différencient à partir des précurseurs communs aux cDCs. Elles expriment le facteur de transcription IRF-4, important pour les cDC2, et son absence affecte leur homéostasie. Cependant, la proximité des mcDCs avec les cDC2 diffère en matière de métabolisme où elles ont des signatures différentes. Les mcDCs sont retrouvées en plus grand nombre dans un modèle murin de diabète auto-immun spontané (NOD) que dans une lignée de souris résistante (C57BL/6). Notre laboratoire a validé que le locus Idd13 du chromosome 2 était lié au nombre de mcDCs, suggérant donc qu’un ou plusieurs gènes de ce locus ont un rôle dans la régulation du nombre de mcDCs. En ciblant des gènes polymorphiques entre la souris NOD et la souris C57BL/6, nous avons déterminé que le gène Bim, qui code pour une molécule proapoptotique, régule de manière moelle osseuse intrinsèque spécifiquement les mcDCs. Les mcDCs sont donc un sous-type de cDCs spécifiquement régulé par Bim. Ce sous- type de cDCs est une population clé dans les bris de tolérance et comprendre leur homéostasie est primordial pour déterminer leur rôle dans le contrôle de la tolérance immune.Unlike other conventional dendritic cells (cDCs) subtypes, presentation of peptides derived from apoptotic bodies by merocytic dendritic cells (mcDCs) is associated with a break of tolerance. Presentation of peptides derived from pancreatic beta cells by mcDC is linked to diabetes induction. However, when loaded with peptides derived from tumor cells, they allow the reactivation of T cells and the elimination of the tumor. These properties specific to mcDC highlight new aspects in the control of break of tolerance. Understanding their relationships with other DCs and their regulation is important for understanding the mechanisms associated with immune tolerance. We have determined that mcDCs are cDCs. mcDCs are short-lived cells able to induce an allogeneic response. They express the specific cDC transcription factor, Zbtb46. mcDCs are differentiated from the cDC common precursors. They express and require IRF-4 for their homeostasis, a transcription factor associated with cDC2 differentiation. However, the proximity of mcDC to cDC2 differs in terms of metabolism where they have different signatures. mcDCs are found in greater numbers in the mouse model of spontaneous autoimmune diabetes (NOD) than in a resistant line (C57BL/6). Our laboratory validated that the Idd13 locus of chromosome 2 was linked to mcDC number, thus suggesting that one or more genes of this locus have a role in regulating the number of mcDC. By targeting polymorphic genes between the NOD and C57BL/6 mice, we determined that Bim gene, encoding a pro-apoptotic molecule, regulate specifically mcDC in a bone marrow intrinsic manner. Therefore, mcDCs are a subset of cDCs specifically regulated by Bim. This subtype of cDCs is a key player in break of tolerance and understanding their homeostasis is important in determining their role in immune tolerance

Transcriptional regulation of dendritic cell development and function

Dendritic cells (DCs) are sentinel immune cells that form a critical bridge linking the innate and adaptive immune systems. Extensive research addressing the cellular origin and heterogeneity of the DC network has revealed the essential role played by the spatiotemporal activity of key transcription factors. In response to environmental signals DC mature but it is only following the sensing of environmental signals that DC can induce an antigen specific T cell response. Thus, whilst the coordinate action of transcription factors governs DC differentiation, sensing of environmental signals by DC is instrumental in shaping their functional properties. In this review, we provide an overview that focuses on recent advances in understanding the transcriptional networks that regulate the development of the reported DC subsets, shedding light on the function of different DC subsets. Specifically, we discuss the emerging knowledge on the heterogeneity of cDC2s, the ontogeny of pDCs, and the newly described DC subset, DC3. Additionally, we examine critical transcription factors such as IRF8, PU.1, and E2-2 and their regulatory mechanisms and downstream targets. We highlight the complex interplay between these transcription factors, which shape the DC transcriptome and influence their function in response to environmental stimuli. The information presented in this review provides essential insights into the regulation of DC development and function, which might have implications for developing novel therapeutic strategies for immune-related diseases

Immature and mature bone marrow-derived dendritic cells exhibit distinct intracellular mechanical properties

ABSTRACT: Dendritic cells (DCs) patrol the organism at an immature stage to detect the presence of pathogens. Once activated, these mature DCs reach the lymph nodes to activate antigen-specific T lymphocytes and thus initiate an adaptative immune response to control the pathogen. The migration of both immature and mature DCs is a key process for their optimal function. DC migration requires transit through narrow constrictions that is allowed by their high local and global deformation capabilities. In addition to cytoplasmic changes, the nucleus mechanical properties also have a major impact for cellular migration and motility. Yet, nucleus intracellular mobility of dendritic cells or its variation upon maturation have not been investigated. Our study defines the biophysical phenotypic variations of dendritic cells upon maturation using interferometric deformability cytometry. This method characterizes different cellular mechanical properties, such as elongation and nucleus offset, by assessing the refractive index spatial distribution of shear-induced deformed cells. By using these parameters, our data suggest that in vitro bone marrow derived dendritic cell (BMDC) maturation induces cell stiffening and reduces nucleus mobility, allowing to distinguish immature and mature dendritic cells. Overall, our method provides insights on intracellular mechanical properties of two dendritic cell states

Collagen analogs with phosphorylcholine are inflammation-suppressing scaffolds for corneal regeneration from alkali burns in mini-pigs

The long-term survival of biomaterial implants is often hampered by surgery-induced inflammation that can lead to graft failure. Considering that most corneas receiving grafts are either pathological or inflamed before implantation, the risk of rejection is heightened. Here, we show that bioengineered, fully synthetic, and robust corneal implants can be manufactured from a collagen analog (collagen-like peptide-polyethylene glycol hybrid, CLP-PEG) and inflammation-suppressing polymeric 2-methacryloyloxyethyl phosphorylcholine (MPC) when stabilized with the triazine-based crosslinker 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The resulting CLP-PEG-MPC implants led to reduced corneal swelling, haze, and neovascularization in comparison to CLP-PEG only implants when grafted into a mini-pig cornea alkali burn model of inflammation over 12 months. Implants incorporating MPC allowed for faster nerve regeneration and recovery of corneal sensation. CLP-PEG-MPC implants appear to be at a more advanced stage of regeneration than the CLP-PEG only implants, as evidenced by the presence of higher amounts of cornea-specific type V collagen, and a corresponding decrease in the presence of extracellular vesicles and exosomes in the corneal stroma, in keeping with the amounts present in healthy, unoperated corneas

Immature and mature bone marrow-derived dendritic cells exhibit distinct intracellular mechanical properties

Abstract Dendritic cells (DCs) patrol the organism at an immature stage to detect the presence of pathogens. Once activated, these mature DCs reach the lymph nodes to activate antigen-specific T lymphocytes and thus initiate an adaptative immune response to control the pathogen. The migration of both immature and mature DCs is a key process for their optimal function. DC migration requires transit through narrow constrictions that is allowed by their high local and global deformation capabilities. In addition to cytoplasmic changes, the nucleus mechanical properties also have a major impact for cellular migration and motility. Yet, nucleus intracellular mobility of dendritic cells or its variation upon maturation have not been investigated. Our study defines the biophysical phenotypic variations of dendritic cells upon maturation using interferometric deformability cytometry. This method characterizes different cellular mechanical properties, such as elongation and nucleus offset, by assessing the refractive index spatial distribution of shear-induced deformed cells. By using these parameters, our data suggest that in vitro bone marrow derived dendritic cell (BMDC) maturation induces cell stiffening and reduces nucleus mobility, allowing to distinguish immature and mature dendritic cells. Overall, our method provides insights on intracellular mechanical properties of two dendritic cell states

Immature human dendritic cells enhance their migration through KCa3.1 channel activation

International audienceMigration capacity is essential for dendritic cells (DCs) to present antigen to T cells for the induction of immune response. The DC migration is supposed to be a calcium-dependent process, while not fully understood. Here, we report a role of the KCa3.1/IK1/SK4 channels in the migration capacity of both immature (iDC) and mature (mDC) human CD14 +-derived DCs. KCa3.1 channels were shown to control the membrane potential of human DC and the Ca 2+ entry, which is directly related to migration capacities. The expression of migration marker such as CCR5 and CCR7 was modified in both types of DCs by TRAM-34 (100 nM). But, only the migration of iDC was decreased by use of both TRAM-34 and KCa3.1 siRNA. Confocal analyses showed a close localization of CCR5 with KCa3.1 in the steady state of iDC. Finally, the implication of KCa3.1 seems to be limited to the migration capacities as T cell activation of DCs appeared unchanged. Altogether, these results demonstrated that KCa3.1 channels have a pro-migratory effect on iDC migration. Our findings suggest that KCa3.1 in human iDC play a major role in their migration and constitute an attractive target for the cell therapy optimization

Guidelines for mouse and human DC generation

International audienc