Description du projet
Mieux comprendre les cellules tueuses naturelles qui résident dans les tissus
Les cellules tueuses naturelles (ou cellules NK) sont connues pour leur rôle dans l’immunité anti-tumorale, pour leur capacité à lutter contre les infections et pour leur impact sur les issues d’une grossesse. De plus en plus de preuves issues de modèles murins soulignent la présence de cellules NK qui résident dans les tissus, mais les mécanismes qui gouvernent leur maintenance et leur régulation demeurent mal compris, notamment chez l’être humain. Le projet RESIDE, financé par l’UE, entend caractériser des sous-ensembles de cellules NK humaines qui résident de manière permanente dans le foie et l’utérus. Les scientifiques étudieront le mécanisme qui sous-tend la résidence au sein des tissus et la recirculation de ces cellules. À l’aide d’un modèle de microvascularisation en 3D, ils identifieront également les facteurs qui régulent l’activité des cellules NK résidant dans les tissus.
Objectif
Natural killer (NK) cells contribute to tumor and antiviral immunity, regulate immune homeostasis, and impact on pregnancy success. These functions are in many instances performed in peripheral organs. Recent pioneering research in mouse models has revealed the existence and self-maintenance of tissue-resident (TR) NK cells. Although similar mechanisms are assumed to occur in humans, this has never been formally demonstrated and with our diverse infection history and active microbiota the human setting is considerably more complex. Me and my group have recently identified and characterized presumed TR NK cells in human liver and uterus. Here, we seek to challenge the prevailing concept from the mouse of how TR is formed, regulated, and maintained by taking advantage of world-unique surgical procedures for addressing lymphocyte tissue-residency, such as uterus transplantation and a novel liver surgery creating a human parabiosis situation, combined with single-cell technologies. In these settings, we will determine the detailed characteristics of subsets of NK cells permanently residing in tissues. With the different time windows as well as tissue sites presented by the clinical procedures, we will also assess kinetics of NK cell tissue repopulation. Furthermore, we aim to provide mechanistic insight into NK cell recirculation patterns by studying tissue-draining lymph fluid. Finally, we will study functional regulation of NK cell tissue-residency based on data from targeted single-cell RNAseq across multiple human tissues. The relevance of suspected and novel factors in regulating TR NK cells will be studied in a 3D microvasculature model combined with siRNA-based silencing of candidate genes. TR immune cells are poised to instantly deliver immune responses upon tumor and pathogen challenges while also being drivers of inflammation and autoimmunity in peripheral organs. Thus, this proposal has the potential to provide ground-breaking new knowledge in these areas.
Champ scientifique
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
17177 Stockholm
Suède