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，新鉴定的称为“CD4+CD25+抑制”或“调节”T细胞的T细胞群体在免疫耐受或抑制异常免疫反应中发挥重要作用。尽管抑制机制很大程度上未知，但抑制性 T 细胞需要物理接触其靶细胞才能抑制它们。为了接触靶细胞，抑制性 T 细胞必须迁移到其靶细胞存在或迁移到的组织部位。这意味着CD4+CD25+抑制性T细胞的迁移行为在一定程度上可以决定它们在体内的抑制活性。然而，这些抑制性 T 细胞相对于它们的靶细胞（例如初始 T 细胞、记忆 T 细胞和效应 T 细胞）在体内迁移到何处仍有待确定。此外，抑制性 T 细胞可能会产生未知的化学引诱剂来招募靶细胞。我们发现CD4+CD25+T细胞表达多种不同的趋化因子受体， 并且它们由表达不同趋化因子受体的多个子集组成。我们假设抑制性 T 细胞由迁移到不同免疫反应位点的异质子集组成（例如全身途径与粘膜途径；淋巴途径与非淋巴途径），并且抑制性 T 细胞的组织特异性运输能力显着有助于它们在体内的抑制活性。为了检验这一假设，我们将首先对 CD4+CD25+ 抑制性 T 细胞进行全面的体外和体内运输研究，以确定对其组织特异性运输重要的趋化因子和趋化因子受体。接下来我们将设计或操纵 CD4+CD25+ 抑制性 T 细胞的运输行为。为了实现这一目标，我们将 1) 将新的趋化因子受体引入 CD4+CD25+ 抑制性 T 细胞，2) 下调现有的趋化因子受体，以确定增加或抑制 T 细胞中 CD4+CD25+ 抑制性 T 细胞活性的迁移行为。诱发肠道炎症和移植物抗宿主病。这些研究有可能提供有关 CD4+CD25+ 抑制性 T 细胞的器官或组织特异性运输及其对免疫耐受的影响的重要信息。