Differential IRF8 Transcription Factor Requirement Defines Two Pathways of Dendritic Cell Development in Humans

The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL+ SIGLEC6+ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using highdimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c+ DC) heterogeneity originates from two distinct pathways of development. The lymphoidprimed IRF8hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL+ SIGLEC6+ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency

Ontogenic, phenotypic and functional characterization of dendritic cells and macrophages in skin squamous cell carcinoma

Les carcinomes épidermoïdes cutanés (CEC) sont des cancers invasifs du kératinocyte qui se développent suite à la subversion du système immunitaire. Une reprogrammation de l’immunité antitumorale par stimulation locale des cellules dendritiques (DC) et des macrophages pourrait être bénéfique. Dans ce contexte, l’objectif de ma thèse a été de comprendre l’hétérogénéité ontogénique, phénotypique et fonctionnelle de ces cellules immunitaires au cours de la carcinogenèse cutanée afin de développer des approches thérapeutiques les stimulant. Nous avons, d’abord, caractérisé les macrophages de la peau de souris et infiltrant les CEC chez l’homme. Nous avons identifié par cytométrie en flux spectrale une population de macrophages matures, autofluorescents et résidents de la peau de souris. Ces macrophages résidents présentent une polarisation fonctionnelle d’homéostasie et de réparation tissulaire. Dans les CEC humains, les macrophages autofluorescents semblent avoir les mêmes caractéristiques que leurs équivalents dans la peau de souris. Dans une seconde étude, nous avons mis en évidence que les DC associées aux tumeurs sont dysfonctionnelles. Une immunothérapie locale composée d’un agoniste de TLR9 et d’un anticorps bloquant la signalisation sous le récepteur à l’IL-10 induit la régression de tumeurs cutanées. Cette approche permet la reprogrammation fonctionnelle des DC et la génération de lymphocytes T CD8+ producteurs d’IFNγ, de TNFα et d’IL-17. Ces résultats mettent en évidence l’hétérogénéité fonctionnelle des cellules myéloïdes dans la peau et les CEC. Leur reprogrammation fonctionnelle permettrait le développement de nouvelles thérapeutiques contre les CEC chez l’homme.Skin Squamous cell carcinoma (sSCC) are invasive keratinocyte tumor that develop after immune system subversion. The reprogrammation of anti-tumoral immunity using local stimulation of dendritic cells (DC) and macrophages could be useful. In this line, the aim of my thesis was to understand ontogenic, phenotypic and functional heterogeneity of these cell subsets along skin carcinogenesis to develop new immunotherapies. First, we characterized skin macrophage subsets in mouse and those infiltrating sSCC in human. Using spectral flow cytometry, we identified matured autofluorescent tissue-resident macrophages. These macrophages are anti-inflammatory polarized. In human sSCC, autofluorescent macrophages seem to have same properties that their mouse counterparts. In second study, we identified tumor-infiltrating DC with altered functions. We used a local immunotherapy composed by a TLR9 agonist and blocking antibody against α-chain of IL-10 receptor. This combination induced tumor regression through DC reprogrammation and IFNγ+, TNFα+ IL17A+ T CD8+ lymphocyte generation. These results highlight functional myeloid heterogeneity in skin and sSCC. Their reprogrammation could promote the development of immunotherapies against sSCC in human

L'Erythème pigmentaire fixe (étude comparative des données de la banque française de pharmacovigilance et de la littérature internationale)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Introduction : Pensée et représentation de l’optimum au temps des Lumières (1680-1789)

Optimum thinking and its representation in the Age of Enlightenment (1680-1789) is the follow-up to a symposium held at the University of Basel in spring 2021. The aim was to examine the notion of optimum in eighteenth-century discourse, i.e., at its emergence. However, there was no univocal theorization of the concept at this time. Instead, it has quietly established itself as a "discourse operator" rather than a theoretical notion. This is why the optimum remains largely underexplored today, although central to many fields of knowledge. This introduction aims to show how different discursive constructs developed in the eighteenth century due to preconceptions of the optimum rather than the notion of the optimum itself. Without claiming exhaustiveness or to exhaust any of the domains covered, the introduction reviews specific fields of knowledge that all involve optima: engineering in the seventeenth and eighteenth centuries stands out as an exemplary field to seek the best possible relationship between effort and effect. In the natural sciences, following the development of Newtonian physics, the question arose as to whether the whole of nature was not an optimal machine. The theology of Leibniz and Pope posed the same question about the metaphysical issues of evil, divine justice, and human happiness. Finally, the political and social thinking of the Enlightenment, from Mandeville to Smith via Montesquieu, raised the question of the economy of passions and the best way to organize the State. Finally, the Physiocrats, having discovered the proper laws of nature, had only to promulgate the optimal form of government. Through these different fields, we highlight the cross-disciplinary dimension of the notion of the optimum and how it informs various discourse operations whose forms extend into the 21st century

Engineered niches support the development of human dendritic cells in humanized mice

International audienceClassical dendritic cells (cDCs) are rare sentinel cells specialized in the regulation of adaptive immunity. Modeling cDC development is crucial to study cDCs and harness their therapeutic potential. Here we address whether cDCs could differentiate in response to trophic cues delivered by mesenchymal components of the hematopoietic niche. We find that mesenchymal stromal cells engineered to express membrane-bound FLT3L and stem cell factor (SCF) together with CXCL12 induce the specification of human cDCs from CD34+ hematopoietic stem and progenitor cells (HSPCs). Engraftment of engineered mesenchymal stromal cells (eMSCs) together with CD34+ HSPCs creates an in vivo synthetic niche in the dermis of immunodeficient mice driving the differentiation of cDCs and CD123+AXL+CD327+ pre/AS-DCs. cDC2s generated in vivo display higher levels of resemblance with human blood cDCs unattained by in vitro-generated subsets. Altogether, eMSCs provide a unique platform recapitulating the full spectrum of cDC subsets enabling their functional characterization in vivo

Que la lumière soit. Et si ce n’était plus seulement vrai !

International audienceThe last decade has been an era of accelerated technological progress for flow cytometry. New technologies have been developed such as mass cytometry in which standard fluorochromes have been replaced by lanthanide-based non-radioactive metals and by spectral cytometry that measures the complete fluorescence spectrum. In this review, we schematically describe conventional, mass and spectral cytometry and present the plus and minus of each technology

NKp46+ Innate Lymphoid Cells Dampen Vaginal CD8 T Cell Responses following Local Immunization with a Cholera Toxin-Based Vaccine

International audienceInnate and adaptive immune cells work in concert to generate efficient protection at mucosal surface. Vaginal mucosa is an epithelial tissue that contains innate and adaptive immune effector cells. Our previous studies demonstrated that vaginal administration of Cholera toxin -based vaccines generate antigen-specific CD8 T cells through the stimulation of local dendritic cells (DC). Innate lymphoid cells (ILC) are a group of lymphocytes localized in epithelial tissues that have important immune functions against pathogens and in tissue homeostasis. Their contribution to vaccine-induced mucosal T cell responses is an important issue for the design of protective vaccines. We report here that the vaginal mucosa contains a heterogeneous population of NKp46+ ILC that includes conventional NK cells and ILC1-like cells. We show that vaginal NKp46+ ILC dampen vaccine-induced CD8 T cell responses generated after local immunization. Indeed, in vivo depletion of NKp46+ ILC with anti-NK1.1 antibody or NKG2D blockade increases the magnitude of vaginal OVA-specific CD8 T cells. Furthermore, such treatments also increase the number of DC in the vagina. NKG2D ligands being expressed by vaginal DC but not by CD8 T cells, these results support that NKp46+ ILC limit mucosal CD8 T cell responses indirectly through the NKG2D-dependent elimination of vaginal DC. Our data reveal an unappreciated role of NKp46+ ILC in the regulation of mucosal CD8 T cell responses