Periodic Reporting for period 2 - RegNK (Regulation of NK cell function)
Berichtszeitraum: 2022-06-01 bis 2023-11-30
To accomplish this goal, three research objectives are proposed: (1) to characterize the mechanisms by which interactions between HLA-DP molecules and NKp44 enable NK cells to recognize HBV-infected cells; (2) to determine the role of NKp44+ NK cells in regulating immune responses during GvHD and autoimmune diseases; and (3) to identify novel peptide-dependent interactions between NK cell receptors and HLA-II that regulate NK cell function. Since the beginning of the project, we have made significant progress towards all three objectives.
Objective 1: to characterize the mechanisms by which interactions between HLA-DP molecules and NKp44 enable NK cells to recognize HBV-infected cells
For this objective, we have successfully established hepatocyte organoid models, and co-culture systems between NK cells and hepatocytes. We furthermore established in vitro models to investigate the lysis of hepatocytes by NK cells, and the consequences of viral infections. We are currently in the process to optimize infection protocols for productive HBV infection of hepatocyte organoids.
Objective 2: to determine the role of NKp44+ NK cells in regulating immune responses during GvHD and autoimmune diseases
Within this objective, we have now completed two studies. One study investigated the role of interactions between NKp44 and HLA-DP molecules in ulcerative colitis, and demonstrated that HLA-DP expressed on epithelial cells enables tissue damage by NKp44+ NK cells. These studies combined patient cohorts, intestinal organoid systems and co-cultures with NK cells, and were recently published in Gastroenterology. The second study investigated the role of interactions between NKp44 and HLA-DP in primary sclerosing cholangitis (PSC), and autoimmune disease of the liver. In these studies we identified a novel HLA-DP risk allotype for PSC, and demonstrated using in vitro studies that HLA-DP is upregulated on cholangiocytes in individuals with PSC, and can activate NKp44+ NK cells. This study was recently published in Gut. A third project investigating the role of NKp44+ NK cells in GvHD is ongoing.
Objective 3: to identify novel peptide-dependent interactions between NK cell receptors and HLA-II that regulate NK cell function.
In objective 3, we have started to identify several novel peptides that are presented by HLA-DP, focusing initially on HLA-DP401, and started to determine their consequences for NKp44 binding and NKp44+ NK cell activation. Work on this objective will be to focus during the remaining funding period of RegNK.