HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

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-DP401 pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301 pos IECs. HLA-DP401 pos 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-DP301 pos 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.