CCR6 Regulation of Intestinal T Lymphocyte Development

CCR6 对肠道 T 淋巴细胞发育的调节

• 批准号: 6775267
• 负责人: IFOR R WILLIAMS
• 金额: $ 29.87万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6775267
• 关键词: T lymphocyte; bone marrow; bromodeoxyuridine; cell differentiation; cell proliferation; chemokine receptor; gene targeting; genetically modified animals; interferon gamma; interleukin 10; laboratory mouse; protein structure function

DESCRIPTION (provided by applicant): The intestinal epithelium is home to specialized subsets of intraepithelial T lymphocytes (IEL) that provide essential regulatory and effector functions. Chemokines and chemokine receptors play pivotal roles in guiding the trafficking of T cells during their differentiation from precursors in lymphoid tissues and their subsequent migration to extralymphoid sites. Absence of the CC chemokine receptor 6 (CCR6) in mice leads to perturbations of mucosal immunity including an increase in the number of small intestinal IEL. IEL from CCR6 deficient mice display selective expansion of the alpha beta TCR IEL subsets expressing CD8alpha/alpha that can develop from precursors in intestinal cryptopatches through an extrathymic differentiation pathway. Preliminary studies using mutant mice with an EGFP knock in mutation at the CCR6 locus demonstrate that CCR6 is expressed on a majority of the IEL precursors found in cryptopatches, but is absent from mature IEL. The central objective of the proposed studies is to identify the mechanisms by which absence of CCR6 leads to dysregulated local T cell differentiation in the intestine. The differentiation potential of IEL precursors from CCR6 deficient and wild-type mice will be compared using a competitive adoptive transfer model in which both types of precursor cells are allowed to differentiate into mature IEL following transfer into mice that lack endogenous cryptopatches and intestinal IEL (CD132 null mice that lack the common gamma chain of the IL-2 receptor). The first specific aim is to determine the stage of IEL differentiation at which CCR6 deficient IEL precursors begin to show preferential expansion compared to wild-type IEL precursors. Functional properties (cytokine production, lytic activity, and proliferative rate) of IEL derived from CCR6 null or wild type precursors will also be compared. The second aim is to investigate the potential precursor-product relationship between CCR6+ and CCR6- c-kit+ intestinal lymphocyte precursors by comparing their relative maturity and differentiation potential. Mechanistic insights into the CCR6 dependent regulatory pathway that normally maintains homeostatic control over intestinal IEL may lead to identification of new types of chemokine receptor targeted pharmacological manipulations useful in the treatment of human inflammatory bowel disease.

描述（由申请人提供）：肠上皮是上皮内 T 淋巴细胞 (IEL) 专门亚群的所在地，这些亚群提供必要的调节和效应功能。趋化因子和趋化因子受体在引导 T 细胞从淋巴组织中的前体细胞分化以及随后迁移到淋巴外位点的过程中发挥着关键作用。 小鼠中 CC 趋化因子受体 6 (CCR6) 的缺失会导致粘膜免疫紊乱，包括小肠 IEL 数量增加。来自 CCR6 缺陷小鼠的 IEL 显示出表达 CD8α/α 的 alpha beta TCR IEL 亚群的选择性扩增，这些亚群可以通过胸腺外分化途径从肠道隐斑中的前体发育而来。 使用 CCR6 基因座上具有 EGFP 敲入突变的突变小鼠进行的初步研究表明，CCR6 在密码补丁中发现的大多数 IEL 前体上表达，但在成熟的 IEL 中不表达。拟议研究的中心目标是确定 CCR6 缺失导致肠道局部 T 细胞分化失调的机制。将使用竞争性过继转移模型来比较来自 CCR6 缺陷型小鼠和野生型小鼠的 IEL 前体细胞的分化潜力，在该模型中，两种类型的前体细胞在转移到缺乏内源性密码贴片和肠道 IEL 的小鼠（缺乏 IL-2 受体的共同伽玛链的 CD132 缺失小鼠）后都可以分化为成熟的 IEL。第一个具体目标是确定 IEL 分化的阶段，在该阶段，与野生型 IEL 前体相比，CCR6 缺陷的 IEL 前体开始显示出优先扩增。 还将比较源自 CCR6 无效或野生型前体的 IEL 的功能特性（细胞因子产生、裂解活性和增殖率）。 第二个目的是通过比较 CCR6+ 和 CCR6- c-kit+ 肠道淋巴细胞前体的相对成熟度和分化潜力，研究它们之间潜在的前体-产物关系。对通常维持肠道 IEL 稳态控制的 CCR6 依赖性调节途径的机制了解可能会导致识别新型趋化因子受体靶向药理操作，可用于治疗人类炎症性肠病。