Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Division of Infectious Disease, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
J Clin Invest. 2020 May 1;130(5):2377-2390. doi: 10.1172/JCI127242.
Colitis caused by Clostridium difficile infection is a growing cause of human morbidity and mortality, especially after antibiotic use in health care settings. The natural immunity of newborn infants and protective host immune mediators against C. difficile infection are not fully understood, with data suggesting that inflammation can be either protective or pathogenic. Here, we show an essential role for IL-17A produced by γδ T cells in host defense against C. difficile infection. Fecal extracts from children with C. difficile infection showed increased IL-17A and T cell receptor γ chain expression, and IL-17 production by intestinal γδ T cells was efficiently induced after infection in mice. C. difficile-induced tissue inflammation and mortality were markedly increased in mice deficient in IL-17A or γδ T cells. Neonatal mice, with naturally expanded RORγt+ γδ T cells poised for IL-17 production were resistant to C. difficile infection, whereas elimination of γδ T cells or IL-17A each efficiently overturned neonatal resistance against infection. These results reveal an expanded role for IL-17-producing γδ T cells in neonatal host defense against infection and provide a mechanistic explanation for the clinically observed resistance of infants to C. difficile colitis.
艰难梭菌感染引起的结肠炎是导致人类发病率和死亡率上升的一个原因，尤其是在医疗机构使用抗生素后。新生儿对艰难梭菌感染的天然免疫和保护性宿主免疫介质尚未得到充分理解，有数据表明炎症可能具有保护作用，也可能具有致病性。在这里，我们发现 γδ T 细胞产生的白细胞介素-17A 在宿主抵御艰难梭菌感染方面起着至关重要的作用。艰难梭菌感染患儿的粪便提取物显示白细胞介素-17A 和 T 细胞受体 γ 链表达增加，并且在感染后小鼠的肠道 γδ T 细胞中有效地诱导了白细胞介素-17 的产生。缺乏白细胞介素-17A 或 γδ T 细胞的小鼠，其艰难梭菌诱导的组织炎症和死亡率明显增加。具有天然扩增的 RORγt+γδ T 细胞以产生白细胞介素-17A 的新生小鼠对艰难梭菌感染具有抗性，而消除 γδ T 细胞或白细胞介素-17A 都有效地推翻了新生小鼠对感染的抗性。这些结果揭示了白细胞介素-17 产生的 γδ T 细胞在新生儿宿主抵御感染方面的扩展作用，并为临床上观察到婴儿对艰难梭菌结肠炎的抗性提供了机制解释。
