1-s2.0-S0016508523047728-main.pdf (8.12 MB)
HLA-DP on epithelial cells enables tissue damage by NKp44+ natural killer cells in ulcerative colitis.
journal contributionposted on 2023-10-03, 12:07 authored by Martin E Baumdick, Annika Niehrs, Frauke Degenhardt, Maria Schwerk, Ole Hinrichs, Ana Jordan-Paiz, Benedetta Padoan, Lucy HM Wegner, Sebastian Schloer, Britta F Zecher, Jakob Malsy, Vinita R Joshi, Christin Illig, Jennifer Schröder-Schwarz, Kimberly J Möller, Hamburg Intestinal Tissue Study Group, Maureen P Martin, Yuko Yuki, Mikki Ozawa, Jürgen Sauter, Alexander H Schmidt, Daniel Perez, Anastasios D Giannou, Mary Carrington, Randall S Davis, Udo Schumacher, Guido Sauter, Samuel Huber, Victor G Puelles, Nathaniel Melling, Andre Franke, International Inflammatory Bowel Disease Genetics Consortium, Marcus Altfeld, Madeleine J Bunders
BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. METHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. RESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. CONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC.
Crick (Grant ID: CC2219, Grant title: Lee CC2219)
Colitis, UlcerativeEpithelial CellsHaplotypesHLA-DP AntigensHumansKiller Cells, NaturalHLA-DPIntestinal OrganoidsNK CellsNKp44Ulcerative ColitisHamburg Intestinal Tissue Study GroupInternational Inflammatory Bowel Disease Genetics ConsortiumLee CC22191103 Clinical Sciences1109 Neurosciences1114 Paediatrics and Reproductive MedicineGastroenterology & Hepatology