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，提供基本的调节和效应功能。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细胞分化到淋巴组织外的过程中起着关键的作用。CC趋化因子受体6(CCR6)的缺失导致小鼠粘膜免疫功能紊乱，包括小肠IEL数量增加。CCR6缺陷小鼠的IEL表现出表达CD8α/α的α-β-TCR IEL亚群的选择性扩张，CD8-α/α可通过胸腺外分化途径从肠道隐窝补片的前体发育而来。利用CCR6基因座有EGFP敲入突变的突变小鼠进行的初步研究表明，CCR6在大多数在密码配对中发现的IEL前体上表达，但在成熟的IEL中缺失。建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。CCR6缺陷小鼠和野生型小鼠的IEL前体细胞的分化潜能将通过竞争性采用转移模型进行比较，在该模型中，两种类型的前体细胞在转移到缺乏内源性加密补片的小鼠和肠道IEL(CD132缺失的小鼠，缺乏IL-2受体的共同伽马链)后，被允许分化为成熟的IEL。第一个具体目的是确定IEL分化的阶段，在这个阶段，CCR6缺陷的IEL前体开始表现出比野生型IEL前体更优先的扩张。还将比较CCR6缺失和野生型前体来源的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能来研究它们之间潜在的前体-产物关系。对CCR6依赖的调控途径的机械性洞察通常维持对肠道IEL的稳态控制，可能导致识别新型趋化因子受体靶向的药理操作，用于治疗人类炎症性肠病。

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.