γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice.
γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice.
复制标题
DOI：
10.1053/j.gastro.2015.02.053
复制
发表时间：
2015-06
期刊：
影响因子：
29.4
通讯作者：
Turner JR
中科院分区：
文献类型：
--
作者：
Edelblum KL;Singh G;Odenwald MA;Lingaraju A;El Bissati K;McLeod R;Sperling AI;Turner JR
表达γδ T细胞受体（γδ IEL）的上皮内淋巴细胞通过未知机制限制病原体跨肠上皮的易位。我们研究了γδ IEL迁移和与上皮细胞的相互作用是否促进肠道感染期间粘膜屏障的维持。将鼠伤寒沙门氏菌或弓形虫给予γδ T细胞缺陷型（Tcrd KO）、CD 103缺陷型（CD 103 KO）或对照TcrdEGFP C57 BL/6报告小鼠。使用活体显微镜观察GFP标记的γδ T细胞在用DsRed标记的鼠伤寒沙门氏菌感染的小鼠的小肠粘膜内的迁移。产生混合骨髓嵌合体以评估γδ IEL迁移对早期病原体侵袭和慢性全身性感染的影响。活体视频显微镜数据的形态测定分析表明，γδ IEL迅速定位于与细菌直接接触的上皮细胞并保持在其附近。在1小时内，与对照组相比，具有迁移缺陷型occludin KO γδ T细胞的小鼠粘膜内存在更多数量的弓形虫或鼠伤寒沙门氏菌。Tcrd KO小鼠中的病原体侵袭在数量上与具有闭合蛋白缺陷的γδ T细胞的小鼠中的病原体侵袭相似，而CD 103 KO小鼠中的侵袭（其具有增加的γδ T细胞向侧向细胞间隙中的迁移）减少了63%。与γδ T细胞迁移在早期宿主防御中的作用一致，相对于野生型或CD 103 KO γδ IEL的小鼠，闭合蛋白缺陷γδ IEL的小鼠中系统性沙门氏菌病发展更快，严重程度更高。在小鼠中，上皮内迁移至与病原体接触的上皮细胞对于γδ IEL监测和直接宿主防御至关重要。γδ IEL occludin是限制全身性疾病的早期监测所必需的。
Intraepithelial lymphocytes that express the γδ T cell receptor (γδ IELs) limit pathogen translocation across the intestinal epithelium by unknown mechanisms. We investigated whether γδ IEL migration and interaction with epithelial cells promote mucosal barrier maintenance during enteric infection. Salmonella typhimurium or Toxoplasma gondii were administered to γδ T cell-deficient (Tcrd KO), CD103-deficient (CD103 KO), or control TcrdEGFP C57BL/6 reporter mice. Intravital microscopy was used to visualize migration of GFP-tagged γδ T cells within the small intestinal mucosa of mice infected with DsRed-labeled S typhimurium. Mixed bone marrow chimeras were generated to assess the effects of γδ IEL migration on early pathogen invasion and chronic systemic infection. Morphometric analyses of intravital video microscopy data showed that γδ IELs rapidly localized to and remained near epithelial cells in direct contact with bacteria. Within 1 hr, greater numbers of T gondii or S typhimurium were present within mucosae of mice with migration-defective occludin KO γδ T cells, compared with controls. Pathogen invasion in Tcrd KO mice was quantitatively similar to that in mice with occludin-deficient γδ T cells, whereas invasion in CD103 KO mice, which have increased migration of γδ T cells into the lateral intercellular space, was reduced by 63%. Consistent with a role of γδ T cell migration in early host defense, systemic salmonellosis developed more rapidly and with greater severity in mice with occludin-deficient γδ IELs, relative to those with wild-type or CD103 KO γδ IELs. In mice, intraepithelial migration to epithelial cells in contact with pathogens is essential to γδ IEL surveillance and immediate host defense. γδ IEL occludin is required for early surveillance that limits systemic disease.