潘尼斯电池
上皮内淋巴细胞
ATG16L1
生物
离体
免疫学
肠粘膜
细胞生物学
免疫系统
体内
细胞凋亡
医学
遗传学
自噬
内科学
生物化学
小肠
作者
Yu Matsuzawa-Ishimoto,Xiaomin Yao,Akiko Koide,Beatrix Ueberheide,Jordan Axelrad,Bernardo Sgarbi Reis,Roham Parsa,Jessica A. Neil,Joseph C. Devlin,Eugene Rudensky,M. Zahidunnabi Dewan,Michael Cammer,Richard S. Blumberg,Yi Ding,Kelly V. Ruggles,Daniel Mucida,Shohei Koide,Ken Cadwell
出处
期刊:Nature
[Springer Nature]
日期:2022-10-05
卷期号:610 (7932): 547-554
被引量:14
标识
DOI:10.1038/s41586-022-05259-y
摘要
Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn's disease, a major type of inflammatory bowel disease1-7. Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium8,9. This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn's disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte-epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1 risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death.
科研通智能强力驱动
Strongly Powered by AbleSci AI