HLA-DP on epithelial cells enables tissue damage by NKp44+ natural killer cells in ulcerative colitis.
Creators: name: Baumdick, Martin E
name: Niehrs, Annika
name: Degenhardt, Frauke
name: Schwerk, Maria
name: Hinrichs, Ole
name: Jordan-Paiz, Ana
name: Padoan, Benedetta
name: Wegner, Lucy HM
name: Schloer, Sebastian
name: Zecher, Britta F
name: Malsy, Jakob
name: Joshi, Vinita R
name: Illig, Christin
name: Schröder-Schwarz, Jennifer
name: Möller, Kimberly J
name: Group, Hamburg Intestinal Tissue Study
name: Martin, Maureen P
name: Yuki, Yuko
name: Ozawa, Mikki
name: Sauter, Jürgen
name: Schmidt, Alexander H
name: Perez, Daniel
name: Giannou, Anastasios D
name: Carrington, Mary
name: Davis, Randall S
name: Schumacher, Udo
name: Sauter, Guido
name: Huber, Samuel
name: Puelles, Victor G
name: Melling, Nathaniel
name: Franke, Andre
name: Consortium, International Inflammatory Bowel Disease Genetics
name: Altfeld, Marcus
name: Bunders, Madeleine J
Publisher: name: The Francis Crick Institute
Year: 2023
Subjects: classificationCode: Gene Expression
subject: Gene Expression
classificationCode: Immunology
subject: Immunology
subject: FOS: Clinical medicine
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Cell Biology
subject: Cell Biology

description: BACKGROUND &amp; 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.