Gut NKp46+ Cells : new members of the emerging family of intestinal lymphoid cells

• Main Author: Reynders, Ana
• Other Authors: Aix-Marseille 2
• Language: en
• Published: 2010
• Subjects: Intestin; NKp46; RoRyt; Il22; LTi cells; NK cells; Listeria monocytogenes
• Online Access: http://www.theses.fr/2010AIX22090/document

Nous avons montré que, dans l'intestin, les cellules exprimant le marqueur spécifique des lymphocytes Natural Killer (NK), NKp46 peuvent être divisées en deux compartiments, par rapport au facteur de transcription RORyt. Les cellules NKp46+RORyt- sont des cellules NK intestinales immatures. Cependant, les cellules NKp46+RORyt- s'apparentent aux cellules "lymphoid tissue-inducer" (LTi), puisqu'elles requièrent RORyt pour leur développement et produisent de l'IL-22, cytokine essentielle pour l'homéostasie et la réponse antimicrobienne épithéliale. Notre recherche actuelle vise à établir les relations ontogéniques et la signature génétique de ces cellules au niveau pan-génomique. La fonction in vivo des cellules NKp46+ intestinales est adressée dans un modèle unique d'infection par voie orale avec Listeria monocytogenes. L'ensemble de nos résultats a montré que les cellules NKp46+ ont une place légitime dans la famille émergente des cellules intestinales de l'immunité innée. === Natural Killer (NK) cells are NKp46+CD3- innate lymphocytes, which exhibit cytotoxicityand cytokine production, mainly IFN-γ, as major effector functions. In mammals, theexpression of natural cytotoxic receptor NKp46 is essentially restricted to NK cellcompartment. However, we showed that in mouse intestine, NKp46 marker defines aheterogeneous cell population, differentially expressing the retinoic acid orphan receptorRORγt. NKp46+RORγt- cells harbor reduced cytotoxicity and IFN-γ production, consistentwith an immature NK cell phenotype. In contrast, NKp46+RORγt+ cells resemble lymphoidtissue inducer cells (LTi) in their developmental requirement for RORγt and their ability toproduce IL-22. This cytokine is critical for epithelial homeostasis and antimicrobial responseat several epithelial sites.By using a genome wide profiling approach, we confirmed that gut NKp46+RORγt- cellsare the only gut NKp46+ cell population related to conventional splenic NK cells, while gutNKp46+RORγt+ cells are linked to LTi cells. Transcriptional signatures specific of distinct gutNKp46+ cell subsets are currently under intensive investigation in order to determine novelfunctional properties.We assessed gut NKp46+ cell subsets in vivo function during oral infection with entericpathogen Listeria monocytogenes (L.m.). Although immune responses to systemic L.minfection have been widely characterized in mice, L.m. cannot breach mouse intestinal barrier,thus limiting the knowledge of early immune responses at the natural site of infection. Using aunique transgenic mouse lineage restoring L.m. intestinal invasiveness, we showed that gutNKp46+RORγt- and NKp46+RORγ t+ cells respond to L.m. infection by producing IFN-γ andIL-22, respectively. Further investigation of the cellular mechanisms leading to gut NKp46+cell subset activation, as well as the contribution of these cells to the control of bacterialdissemination is in progress.Altogether our data provide novel insight into intestinal innate immunity and highlight gutNKp46+ cell subsets as “legitimate” members of the emerging family of intestinal innatelymphoid cells