期刊
GASTROENTEROLOGY
卷 162, 期 3, 页码 877-+出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2021.11.028
关键词
Mucosal Immunology; Gamma Delta T Cells; Cell Extrusion
资金
- National Institute for Research Resources grant [S10RR027022]
- National Institute of Health [R21AI143892, T32AI125185, F30DK121391]
- New Jersey Health Foundation [BB/J004529/1, BB/K018256/1]
- National Health and Medical Research Council
- CRE Digestive Health
- Canadian Institutes for Health Research Foundation Grant
This study uncovers a previously unrecognized role for γδ IELs in facilitating TNF-mediated shedding of apoptotic enterocytes via CD103-mediated extracellular granzyme release.
BACKGROUND & AIMS: Excessive shedding of apoptotic enterocytes into the intestinal lumen is observed in inflam-matory bowel disease and is correlated with disease relapse. Based on their cytolytic capacity and surveillance behavior, we investigated whether intraepithelial lymphocytes expressing the gamma delta T cell receptor (gamma delta IELs) are actively involved in the shedding of enterocytes into the lumen. METHODS: Intravital microscopy was performed on GFP gamma delta T cell reporter mice treated with intraperitoneal lipopolysaccharide (10 mg/kg) for 90 minutes to induce tumor necrosis factor-mediated apoptosis. Cell shedding in various knockout or transgenic mice in the presence or absence of blocking antibody was quantified by immunostaining for ZO-1 funnels and cleaved caspase-3 (CC3). Granzyme A and granzyme B release from ex vivo-stimulated gamma delta IELs was quantified by enzyme-linked immunosorbent assay. Immunostaining for gamma delta T cell receptor and CC3 was performed on duodenal and ileal biopsies from controls and patients with Crohn's disease. RESULTS: Intravital microscopy of lipopolysaccharide-treated mice revealed that gamma delta IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cad-herin, and CD103 knockout or blockade significantly reduced lipopolysaccharide-induced shedding. Furthermore, we found that granzymes A and B, but not perforin, are required for cell shedding. These extracellular granzymes are released by gamma delta IELs both constitutively and after CD103/E-cadherin ligation. Moreover, we found that the frequency of gamma delta IEL localization to CC3-positive enterocytes is increased in Crohn's disease bi-opsies compared with healthy controls. CONCLUSIONS: Our results uncover a previously unrecognized role for gamma delta IELs in facilitating tumor necrosis factor-mediated shedding of apoptotic enterocytes via CD103-mediated extracellular gran-zyme release.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据