Organ-specific migration of CD4+CD25+ regulatory T cells

CD4 CD25 调节性 T 细胞的器官特异性迁移

• 批准号: 7140396
• 负责人: CHANG H KIM
• 金额: $ 21.94万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140396
• 关键词: CD antigens; SCID mouse; cell migration; chemoattractants; chemokine receptor; clinical research; genetically modified animals; graft versus host disease; helper T lymphocyte; immune tolerance /unresponsiveness; immunosuppression; inflammation; intestine disorder; laboratory mouse; leukocyte activation /transformation; organ; receptor expression; suppressor T lymphocyte

DESCRIPTION (provided by applicant): Recent studies suggest that newly identified populations of T cells termed "CD4+CD25+ suppressor" or "regulatory" T cells play important roles in immune tolerance or suppression of aberrant immune responses. Although the mechanism of suppression is largely unknown, suppressor T cells need to physically contact their target cells to suppress them. In order to contact target cells, suppressor T cells must migrate to tissue sites where their target cells are present or migrate to. This implies that the migration behavior of CD4+CD25+ suppressor T cells, in part, can determine their suppressive activity in vivo. However, it remains to be determined where these suppressor T cells migrate to in vivo relative to their target cells such as naive, memory and effector T cells. Furthermore, suppressor T cells may produce yet unknown chemoattractants to recruit target cells. We have found that CD4+CD25+ T cells express a number of different chemokine receptors, and that they are composed of multiple subsets expressing different chemokine receptors. We hypothesize that suppressor T cells are composed of heterogeneous subsets migrating to different sites of immune responses (e.g. systemic vs. mucosal routes; lymphoid vs. non-lymphoid routes), and that the tissue-specific trafficking ability of suppressor T cells significantly contributes to their suppressive activity in vivo. To test this hypothesis we will first carry out comprehensive in vitro and in vivo trafficking studies of CD4+CD25+ suppressor T cells to identify chemokines and chemokine receptors important for their tissue-specific trafficking. We will next engineer or manipulate trafficking behaviors of CD4+CD25+ suppressor T cells. To achieve this, we will 1) introduce new chemokine receptors into CD4+CD25+ suppressor T cells and 2) down-regulate existing chemokine receptors to identify the migration behavior that increases or inhibits the activity of CD4+CD25+ suppressor T cells in T cell-induced intestinal inflammation and graft-versus-host disease. These studies have the potential to provide important information on organ or tissue-specific trafficking of CD4+CD25+ suppressor T cells and its impact on immune tolerance.

描述（由申请人提供）：最近的研究表明，新确定的称为“ CD4+ CD25+抑制剂”或“调节性” T细胞的T细胞的群体在免疫耐受性或抑制异常免疫反应中起着重要作用。尽管抑制的机制在很大程度上是未知的，但抑制T细胞需要物理接触其靶细胞以抑制它们。为了接触靶细胞，抑制T细胞必须迁移到存在或迁移到目标细胞的组织部位。这意味着CD4+ CD25+抑制T细胞的迁移行为部分可以确定它们在体内的抑制活性。但是，这些抑制剂T细胞相对于幼稚，记忆和效应T细胞等靶细胞迁移到体内迁移尚有待确定。此外，抑制T细胞可能会产生未知的趋化剂来募集靶细胞。我们发现CD4+ CD25+ T细胞表达许多不同的趋化因子受体， 它们由表达不同趋化因子受体的多个子集组成。我们假设抑制剂T细胞由迁移到免疫反应的不同部位（例如，全身性与粘膜途径；淋巴机与非淋巴途径）的异质子集组成，以及抑制T细胞的组织特异性运输能力显着有助于其在VIVO中的抑制活性。为了检验这一假设，我们将首先对CD4+ CD25+抑制剂T细胞进行全面的体外和体内运输研究，以鉴定趋化因子和趋化因子受体对其组织特异性运输至关重要。我们将下一个工程师或操纵CD4+ CD25+抑制剂T细胞的运输行为。为此，我们将1）将新的趋化因子受体引入CD4+ CD25+抑制剂T细胞中，2）下调现有的趋化因子受体，以确定增加或抑制T细胞诱导的肠道炎症和移植术的T细胞中CD4+ CD25+抑制T细胞活性的迁移行为。这些研究具有有关CD4+ CD25+抑制剂T细胞的器官或组织特异性运输的重要信息及其对免疫耐受性的影响。