Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid

To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3+ T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4+ T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ–derived DCs. This enhanced conversion by LpDCs was dependent on TGF-β and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion

Rôle de l'interferon-gamma dans l'immunité cellulaire anti-microsporidienne. Etude du modèle de la souris déficiente pour le récepteur à l'interferon-gamma, infectée oralement avec la microsporidie Encephalitozoon intestinalis

Pr Dominique Mazier (Présidente), Dr Dominique Buzoni-Gatel (Rapporteur), Pr Christian Vivarès (Rapporteur), Pr Martin Danis (Examinateur), Pr Jean Dupouy-Camet (Examinateur), Dr Isabelle Desportes-Livage (Directeur de thèse)The microsporidium Encephalitozoon intestinalis causes gastrointestinal disease frequently associated with other clinical manifestations in immunocompromised HIV-infected patients. The intestinal mucosa provides the first physiological and immunological line of defense against the parasite. Nevertheless, most of what is known about the immunobiology of microsporidia results from studies realized with mice infected by the intraperitoneal route. Protection against these parasites has been largely associated with the cell-mediated immune response and the production of Th1-type cytokines, in particular gamma interferon (IFN-g). However, the mechanisms whereby IFN-g intervenes in the clearance of microsporidia are still not well understood. We therefore studied and compared the cellular immune response in wild-type and IFN-g receptor knockout (GRKO) mice following oral infection with E. intestinalis. First, we observed in infected wild-type mice which are able to control and eradicate the parasite, 1) the development of a Th1-type cellular immune response at the mucosal level, in the mesenteric lymph nodes and in the spleen; 2) the duodenal production of chemokines known to attract T lymphocytes and macrophages; and 3) an increase in the number of intestinal intraepithelial lymphocytes, which are able to exert cytotoxic activity against E. intestinalis-infected macrophages. In contrast, we showed in GRKO mice 1) a change in the pattern of chemokine expression at the mucocal level;2) a defect in the Th1-type cytokine expression and an earlier and/or higher expression of Th2-type cytokines; and finally 3) a less effective splenic cytotoxic T CD8+ response. Altogether, these results allow us to better understand the role of IFN-g in the antimicrosporidial immunity.La microsporidie Encephalitozoon intestinalis est la cause de diarrhées fréquemment associées à d'autres manifestations, chez les sujets immunodéprimés infectés par le VIH. La muqueuse intestinale constitue la première barrière physiologique et immunologique s'opposant à l'entrée du parasite dans l'organisme. Pourtant, la majorité des connaissances concernant l'immunobiologie des microsporidies résulte d'études effectuées chez la souris infectée par la voie intra-péritonéale. L'immunité protectrice vis-à-vis des microsporidies a largement été associée à la réponse immune cellulaire et à la production de cytokines de type Th1, et plus particulièrement d'IFN-g. Cependant, le ou les mécanismes par lequel l'IFN-g intervient dans le contrôle des microsporidioses reste encore mal caractérisé. Nous avons donc étudié et comparé la réponse immune cellulaire chez les souris sauvages et chez les souris déficientes pour le récepteur à l'IFN-g (GRKO), après infection orale avec E. intestinalis. Dans un premier temps, nous avons observé chez les souris sauvages infectées, capable de contrôler et d'éradiquer le parasite, 1) la mise en place d'une réponse immune cellulaire de type Th1 au niveau de la muqueuse intestinale, des ganglions mésentériques et de la rate ; 2) la production au niveau du duodenum de chimiokines connues pour attirer les lymphocytes T et les macrophages ; et 3) une augmentation du nombre de lymphocytes intraépithéliaux intestinaux, capables d'exercer une activité cytotoxique contre des macrophages infectés par le parasite. Chez les souris GRKO infectées, nous avons montré 1) une altération du profil d'expression des chimiokines au niveau de la muqueuse intestinale ; 2) un défaut d'expression des cytokines Th1 et une expression plus précoce et/ou plus importante des cytokines Th2 au niveau de tous les compartiments étudiés ; et 3) une réponse splénique T CD8+ cytotoxique moins efficace. L'ensemble de ces résultats nous permet de mieux cerner le rôle de l'IFN-g dans l'immunité anti-microsporidienne

Rôle de l'interferon-g(IFN-g) dans l'immunité cellulaire anti-microsporidienne (étude du modèle de la souris déficiente pour le récepteur à l'IFN-g, infectée oralement avec la microsporidie Encephalitozoon intestinalis)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Microbe-dendritic cell dialog controls regulatory T-cell fate.

Each microenvironment is controlled by a specific set of regulatory elements that have to be finely and constantly tuned to maintain local homeostasis. These environments could be site specific, such as the gut environment, or induced by chronic exposure to microbes. Various populations of dendritic cells are central to the orchestration of this control. In this review, we discuss some new findings associating dendritic cells from defined compartments with the induction and control of regulatory T cells in the context of exposure to both commensal and pathogenic microbes.FLWINinfo:eu-repo/semantics/publishe

Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection

Commensal flora can promote both immunity to pathogens and mucosal inflammation. How commensal driven inflammation is regulated in the context of infection remains poorly understood. Here, we show that during acute mucosal infection, Ly6C(hi) inflammatory monocytes acquire a tissue specific regulatory phenotype associated with production of the lipid mediator prostaglandin E(2) (PGE(2)). Notably, in response to commensals, Ly6C(hi) monocytes can directly inhibit neutrophil activation in a PGE(2)-dependent manner. Further, in the absence of inflammatory monocytes, mice develop severe neutrophil-mediated pathology that can be controlled by PGE(2) analog treatment. Complementing these findings, inhibition of PGE(2) led to enhanced neutrophil activation and host mortality. These data demonstrate a previously unappreciated dual action of inflammatory monocytes in controlling pathogen expansion while limiting commensal mediated damage to the gut. Collectively, our results place inflammatory monocyte derived PGE(2) at the center of a commensal driven regulatory loop required to control host-commensal dialogue during inflammation

Intraluminal containment of commensal outgrowth in the gut during infection-induced dysbiosis

SummaryShifts in commensal microbiota composition are emerging as a hallmark of gastrointestinal inflammation. In particular, outgrowth of γ-proteobacteria has been linked to the etiology of inflammatory bowel disease and the pathologic consequences of infections. Here we show that following acute Toxoplasma gondii gastrointestinal infection of mice, control of commensal outgrowth is a highly coordinated process involving both the host response and microbial signals. Notably, neutrophil emigration to the intestinal lumen results in the generation of organized intraluminal structures that encapsulate commensals and limit their contact with the epithelium. Formation of these luminal casts depends on the high-affinity N-formyl peptide receptor, Fpr1. Consequently, after infection, mice deficient in Fpr1 display increased microbial translocation, poor commensal containment, and increased mortality. Altogether, our study describes a mechanism by which the host rapidly contains commensal pathobiont outgrowth during infection. Further, these results reveal Fpr1 as a major mediator of host commensal interaction during dysbiosis