Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1⁺ NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8⁺ T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1⁺/HLA-Bw4⁺ donor cells compared with children receiving non–KIR3DS1⁺/HLA-Bw4⁺ cells. These findings identify the KIR3DS1/HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease.

中文翻译：

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KIR3DS1 指导 NK 细胞介导的针对人类腺病毒感染的保护

人类腺病毒 (HAdVs) 是儿童疾病的主要原因，特别是在同种异体造血干细胞移植 (allo-HSCT) 之后。目前，缺乏针对免疫功能低下宿主中 HAdV 感染的有效疗法。为了破译 HAdV 感染的免疫识别并确定免疫介导控制的新目标，我们使用了基于原代人肠上皮细胞的 HAdV 感染 3D 类器官系统。HLA-F 是激活 NK 细胞受体 KIR3DS1 的功能性配体，它被强烈上调并增强了 KIR3DS1 ⁺ NK 细胞对类器官中 HAdV5 感染细胞的杀伤作用。相比之下，HLA-A 和 HLA-B 在 HAdV5 感染的类器官中响应腺病毒 E3/糖蛋白 19K 显着下调，这与逃避 CD8 ^+一致T细胞。与接受非KIR3DS1 ⁺ / HLA-Bw4 ⁺细胞的儿童相比，接受KIR3DS1 ⁺ / HLA-Bw4 ⁺供体细胞的儿童发生严重 HAdV 疾病的风险降低，HAdV 病毒血症的清除速度更快. 这些发现将 KIR3DS1/HLA-F 轴确定为针对严重 HAdV 疾病的免疫治疗策略的新靶点。