HLA-DP on Epithelial Cells enables Tissue Damage by NKp44 + NK Cells in Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and associated with risk single nucleotide polymorphism 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 3D-organoid co-cultures with human NK cells were employed 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 to controls. IECs in human intestinal 3D-organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared to HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and TNF production by NKp44+ NK cells in co-cultures, resulting in enhanced epithelial cell death compared to HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in co-cultures.

CONCLUSION: Here, we identify 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.