gd IELs in chronic ileitis

项目总结。 维持完整的肠道屏障是防止微生物激活粘膜免疫的关键。在……里面 炎症性肠病，这种屏障被破坏，从而使粘膜免疫系统暴露在 肠腔内容物。上皮细胞脱落或排入血管内的显著增加 管腔已被证明是克罗恩病(CD)患者复发的预测因子。GD上皮内 淋巴细胞(IEL)在上皮室内广泛迁移，作为第一道防线。 抗侵袭性微生物，促进细胞凋亡。尽管gd iels在 小鼠结肠炎模型，这些前哨淋巴细胞在慢性回肠炎的发病机制中的参与 不太清楚。已发表的报告提供了相互矛盾的证据，证明gd iels在 慢性回肠炎的发病机制；然而，我们现在表明，在疾病发生之前，可诱导的gd T细胞耗竭 启蒙会增加杀伤力。此外，对发育成熟的小鼠IEL隔室的详细免疫图谱 自发性cd样回肠炎提示gd iels的丢失与回肠的组织学发病相吻合。 炎症，提示gd IEL的丢失可能是一种始动事件。为了支持这一点，我们观察到一个 CD39+gd Tregs频率降低，同时较少激活的外周Vg1+T细胞渗透到IEL 疾病发展前的隔室。因此，我们建议询问gd iels在 慢性回肠炎的发病机制及相关的细胞和分子机制 CD样回肠炎发展过程中Gd IEL间隔区的调节失调。为了解决这些问题， 我们将利用独特的gd T细胞特异性小鼠模型和活体显微镜来定义gd是如何 IEL的运动和效应器功能在导致慢性回肠炎发病的事件中受到调节。通过 结合时间和细胞特异性基因打靶、尖端实时成像技术和新模型 通过对gd IEL功能的体外分析，我们希望能够清楚地阐明gd IEL在糖尿病的发生发展中的作用。 回肠疾病，并进一步定义在gd IEL亚群中的功能失调 慢性炎症。发展对细胞和分子机制的更好理解 GIEL免疫监测和免疫调节可能阐明未来治疗的更多靶点 旨在加强上皮屏障，防止疾病复发。

PROJECT SUMMARY. Maintenance of an intact intestinal barrier is critical to prevent microbial activation of mucosal immunity. In inflammatory bowel disease, this barrier is compromised, thus exposing the mucosal immune system to the contents of the intestinal lumen. A substantial increase in the shedding or extrusion of epithelial cells into the lumen has been shown to be a predictor of relapse in Crohn’s disease (CD) patients. gd intraepithelial lymphocytes (IEL) migrate extensively within the epithelial compartment to serve as a first line of defense against invasive microorganisms and facilitate apoptotic cell shedding. Although gd IELs are protective in mouse models of colitis, the involvement of these sentinel lymphocytes in the pathogenesis of chronic ileitis is less clear. Published reports provide conflicting evidence regarding the contribution of gd IELs in the pathogenesis of chronic ileitis; however, we now show that inducible depletion of gd T cells prior to disease initiation increases lethality. Further, detailed immunoprofiling of the IEL compartment in mice that develop spontaneous CD-like ileitis indicates that the loss of gd IELs coincides with the histological onset of ileal inflammation, suggesting that loss of gd IELs may be an initiating event. In support of this, we observe a reduction in the frequency of CD39+ gd Tregs, while less activated, peripheral Vg1+ T cells infiltrate the IEL compartment prior to disease development. Therefore, we propose to interrogate the contribution of gd IELs in the pathogenesis of chronic ileitis and elucidate the cellular and molecular mechanisms involved in the dysregulation of the gd IEL compartment during the development of CD-like ileitis. To address these questions, we will take advantage of unique gd T-cell-specific mouse models and intravital microscopy to define how gd IEL motility and effector function are regulated in the events leading up to the onset of chronic ileitis. By combining temporal and cell-specific gene targeting, cutting-edge live imaging techniques, and novel models to analyze gd IEL function ex vivo, we expect to clearly elucidate the contribution of gd IELs to the development of ileal disease and further define the functional dysregulation within gd IEL subpopulations in the context of chronic inflammation. Developing a better understanding of the cellular and molecular mechanisms involved in gd IEL immunosurveillance and immunoregulation may elucidate additional targets for future therapies designed to reinforce the epithelial barrier and prevent disease relapse.