Cytotoxic T cells in Ulcerative Colitis

项目摘要 炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC）， 大约有一百万美国人和全世界数百万人。令人担忧的是，IBD的总体发病率为 在儿童和以前不常见IBD的人群中，IBD的发病率不断上升。除了 肠道炎症的显著损害，受影响的患者患有肠外表现 疾病的风险，内科和外科治疗的发病率，以及结肠癌风险的增加。治疗 对许多患者来说是昂贵且无效的。IBD的发病机制复杂， 明白T细胞在IBD中介导异常适应性免疫应答中的重要性已被充分证实。 然而，尽管已经建立，但T细胞介导疾病的机制仍不清楚。虽然很可能 CD4+ T细胞引导和调节CD8+ T细胞应答，驱动组织损伤的末端效应物是 可能是细胞毒性CD8+ T细胞。我们的提案特别旨在鉴定和研究UC中的效应CD8+ T细胞， 我们提出的细胞是组织损伤的罪魁祸首。我们的团队最近开发了新的工具， 我们可以从单个T细胞中收集前所未有的大量信息，准确识别它们的TCR序列， 并询问其抗原特异性。我们的中心假设是表达Bcl 6的CD8+ T细胞驱动组织 在UC的伤害。此外，我们假设它们对本地衍生的信号做出反应。如果是这样， 这些本地衍生的信号可以被定向为非目标。我们将研究这些假设 通过以下具体目的：1）通过以下方法研究溃疡性结肠炎中肠损伤的机制： 表达bcl 6的CD8+ T细胞的单细胞研究和功能表征。2)研究抗原 通过肠类器官和随机肽筛选的bcl 6表达CD8+ T细胞的特异性。 这些目标的成功实现可能对治疗产生重要影响。拟议的研究是 创新，因为它采用创新方法通过单细胞分析研究UC中的T细胞功能 相同患者中炎症结肠与非炎症结肠的TCR匹配细胞。我们的专业知识和 我们的合作者的专业知识使我们具有进行这些研究的独特资格。

Project Summary Inflammatory bowel diseases (IBD), comprised of Crohn’s disease (CD) and ulcerative colitis (UC), afflict approximately one million Americans and millions more worldwide. Alarmingly, the overall incidence of IBD is increasing, and increasing in children and persons in whom IBD had previously been uncommon. In addition to significant impairment from intestinal inflammation, affected patients suffer from extra-intestinal manifestations of disease, morbidities from medical and surgical treatment, and increased risk of colon cancer. Treatments are costly and ineffective in many patients. The mechanisms of IBD are complex and therefore not well understood. The importance of T cells in mediating aberrant adaptive immune responses in IBD is well established, however, the mechanisms through which T cells mediate disease remain unclear. While it is likely that CD4+ T cells guide and regulate CD8+ T cell responses, the end effectors that drive tissue damage are likely cytotoxic CD8+ T cells. Our proposal specifically aims to identify and study effector CD8+ T cells in UC- the cells we propose are responsible for tissue damage. Our team recently developed novel tools that enable us to glean unprecedented amounts of information from single T cells, accurately identify their TCR sequence, and query their antigen specificity. Our central hypothesis is that Bcl6-expressing CD8+ T cells drive tissue damage in UC. Further, we hypothesize that they are responding to locally derived signals. If so, we reason that these locally derived signals can be pharmacologically targeted. We will investigate these hypotheses through the following specific aims: 1) Investigate mechanisms of intestinal damage in ulcerative colitis through the single-cell study and functional characterization of bcl6-expressing CD8+ T cells. 2) Investigate antigen specificity of bcl6-expressing CD8+ T cells through intestinal organoids and random peptide screening. Successful completion of these aims could have important implications in therapies. The proposed research is innovative because it applies innovative methods to study T cell function within UC through single-cell analysis of TCR-matched cells from inflamed vs. non-inflamed colon within the same patients. Our own expertise and the expertise of our collaborators make us uniquely qualified to perform these studies.