CCR6 Regulation of Intestinal T Lymphocyte Development

描述（由申请人提供）：肠上皮是上皮内T淋巴细胞（IEL）的特殊亚群的家园，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细胞从淋巴组织的前体分化并随后迁移到淋巴外部位的运输过程中起着关键作用。小鼠CC趋化因子受体6 （CCR6）的缺失导致粘膜免疫紊乱，包括小肠IEL数量增加。来自CCR6缺陷小鼠的IEL表现出α β TCR IEL亚群的选择性扩增，表达CD8alpha/alpha，可通过胸腺外分化途径从肠道隐斑的前体发育而来。在CCR6位点有EGFP敲入突变的突变小鼠中进行的初步研究表明，CCR6在大多数在隐斑中发现的IEL前体中表达，但在成熟的IEL中不表达。拟议研究的中心目标是确定缺乏CCR6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比较CCR6缺陷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隐斑和肠道IEL的小鼠（缺乏IL-2受体共同γ链的CD132缺失小鼠）后，允许分化为成熟的IEL。第一个具体目标是确定与野生型IEL前体相比，缺乏CCR6的IEL前体开始表现出优先扩展的IEL分化阶段。我们还将比较来自CCR6零型或野生型前体的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，探讨CCR6+和CCR6- c-kit+的潜在前体-产物关系。对通常维持肠道IEL稳态控制的CCR6依赖性调控途径的机制深入了解，可能有助于鉴定用于治疗人类炎症性肠病的新型趋化因子受体靶向药理学操作。

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.