Description du projet
De nouvelles informations mécanistes sur la fonction des cellules tueuses naturelles
Les cellules tueuses naturelles (NK) sont les composants clés du système immunitaire inné qui reconnaissent les molécules HLA‑I présentes à la suite de cellules cancéreuses ou infectées. De récentes preuves indiquent que le récepteur de cytotoxicité naturelle NKp44 régule également la fonction des cellules NK en interagissant avec les molécules HLA‑II. Le projet RegNK, financé par l’UE, entend étudier ce changement de paradigme dans la fonction des cellules NK dans le cadre des maladies humaines. À l’aide de systèmes organoïdes humains et de technologies protéomiques, les scientifiques étudieront les interactions entre NKp44 et HLA‑II et détermineront leur rôle dans l’infection et l’inflammation. Les résultats ouvriront la voie à de nouveaux traitements à base de cellules NK contre les maladies infectieuses et inflammatoires.
Objectif
The human immune system has evolved sophisticated mechanisms to recognize and eliminate infected, stressed or cancer cells. Presentation of antigens by HLA-I enables the identification of diseased cells by antigen-specific T cells, while changes in HLA-I expression levels are sensed by NK cells. Many human NK cell receptors bind HLA-I; but whether and how NK cells might interact with HLA-II remained unknown. We recently discovered that a subset of commonly expressed HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44, implicating HLA-II in the regulation of NK cells. Remarkably, the strength of NKp44-binding to HLA-DP was dependent on both the HLA-DP allotype and the HLA-DP-presented peptide. The ability of NK cell receptors to bind HLA-II molecules represents a paradigm shift from previous models describing NK cell function largely in the context of HLA-I, and suggests a novel regulatory framework in which NK cells interact directly with HLA-II-expressing cells, including APCs and activated stroma cells. HLA-DP allotypes have been associated with the incidence and outcome of several infectious and inflammatory diseases, and the newly identified interactions between HLA-DP and NKp44 now provide a molecular mechanism implicating NK cells in the pathogenesis of these diseases. As NKp44 and HLA-DP are not expressed in mice, but have evolved recently in primates and humans, studies investigating the underlying mechanisms have to be performed in humans. The applicant proposes an innovative and integrated research program, combining functional immunological and virological approaches with recently developed human organoid systems and proteomics technologies to investigate the impact of interactions between NKp44 and HLA-DP for human diseases, with the ultimate goal to harness NK cells for immunotherapeutic interventions against infections and inflammatory diseases.
Champ scientifique
- natural sciencesbiological scienceszoologymammalogyprimatology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health scienceshealth sciencesinflammatory diseases
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesclinical medicineoncology
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
20251 Hamburg
Allemagne