HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis.
HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis.
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上皮细胞上的 HLA-DP 可导致溃疡性结肠炎中 NKp44 自然杀伤细胞造成组织损伤。
DOI：
10.1053/j.gastro.2023.06.034
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发表时间：
2023
期刊：
影响因子：
29.4
通讯作者：
中科院分区：
文献类型：
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作者：
Baumdick,MartinE;Niehrs,Annika;Degenhardt,Frauke;Schwerk,Maria;Hinrichs,Ole;Jordan-Paiz,Ana;Padoan,Benedetta;Wegner,LucyHM;Schloer,Sebastian;Zecher,BrittaF;Malsy,Jakob;Joshi,VinitaR;Illig,Christin;Schröder-Schwarz,Jennifer;
背景与目的溃疡性结肠炎（UC）的特点是严重的炎症和肠上皮的破坏，并与hla II类单核苷酸多态性的特定风险相关。鉴于最近发现的HLA-DP分子亚群与活化自然杀伤（NK）细胞受体NKp44之间的相互作用，研究了UC和hla - dphaplotypes的遗传关联及其功能意义。方法进行shla - dphaplotype与UC风险相关性分析（UC: n = 13,927; control: n = 26,764）。测定了UC患者和非UC患者肠上皮细胞（IECs）上HLA-DP的表达水平。人类肠道三维（3D）类器官与人类NK细胞共培养，以确定HLA-DP和NKp44相互作用的功能后果。结果在欧洲人群中，hla - dpa1∗01:03-DPB1∗04:01（HLA-DP401）为UC的危险单倍型，hla - dpa1∗01:03-DPB1∗03:01（HLA-DP301）为UC的保护单倍型。UC患者IECs中HLA-DP的表达明显高于对照组。与hla - dp301posiecs相比，来源于hla - dp401posecs的人肠道三维类器官的IECs与NKp44的结合明显更强。类器官中的hla - dp401posiec触发共培养中NKp44+NK细胞的脱颗粒和肿瘤坏死因子产生增加，与hla - dp301类器官中相比，导致上皮细胞死亡增加。阻断HLA-DP401-NKp44相互作用（抗nkp44）可消除共培养中NK细胞的活性。结论：我们发现了一种UC风险khla - dphaplotype，它参与NKp44并激活NKp44+NK细胞，以hla - dphaplotype依赖的方式介导肠上皮细胞的损伤。UC中NKp44和HLA-DP401之间的分子相互作用可以通过治疗干预来减少UC中NKp44+NK细胞介导的肠上皮破坏。
Background & AimsUlcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms inHLA 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 andHLA-DPhaplotypes and their functional implications were investigated.MethodsHLA-DPhaplotype 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.ResultsThese studies identifiedHLA-DPA1∗01:03-DPB1∗04:01(HLA-DP401) as a risk haplotype andHLA-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 fromHLA-DP401posindividuals showed significantly stronger binding of NKp44 compared withHLA-DP301posIECs.HLA-DP401posIECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+NK cells in cocultures, resulting in enhanced epithelial cell death compared withHLA-DP301posorganoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.ConclusionsWe identified an UC riskHLA-DPhaplotype that engages NKp44 and activates NKp44+NK cells, mediating damage to intestinal epithelial cells in anHLA-DPhaplotype–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.