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

描述(申请人提供)：最近的研究表明，新发现的T细胞群被称为“CD4+CD25+抑制者”或“调节性”T细胞，在免疫耐受或抑制异常免疫反应中发挥重要作用。虽然抑制的机制在很大程度上还不清楚，但抑制T细胞需要物理地接触它们的靶细胞来抑制它们。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细胞在体内相对于它们的靶细胞如幼稚T细胞、记忆T细胞和效应性T细胞迁移到哪里仍有待确定。此外，抑制性T细胞可能会产生未知的趋化物质来招募靶细胞。我们发现，CD4+CD25+T细胞表达多种不同的趋化因子受体， 它们由表达不同趋化因子受体的多个亚群组成。我们假设抑制性T细胞是由不同亚群组成的，它们迁移到免疫反应的不同部位(例如全身途径和粘膜途径；淋巴途径和非淋巴途径)，并且抑制T细胞的组织特异性运输能力对它们在体内的抑制活性有重要贡献。为了验证这一假说，我们将首先对CD4+CD25+抑制T细胞进行全面的体外和体内转运研究，以确定对其组织特异性转运至关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T细胞的运输行为。为了实现这一目标，我们将1)向CD4+CD25+抑制T细胞引入新的趋化因子受体，2)下调现有的趋化因子受体，以确定在T细胞诱导的肠炎和移植物抗宿主病中增加或抑制CD4+CD25+抑制T细胞活性的迁移行为。这些研究有可能为CD4+CD25+抑制T细胞在器官或组织中的特异性转运及其对免疫耐受的影响提供重要信息。

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.