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“CD4CD25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CD25抑制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，CD4CD25T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。为了验证这一假设，我们将首先对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CD4CD25抑制T细胞的运输行为。为此，我们将1)向CD4CD25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CD4CD25抑制T细胞活性的迁移行为。这些研究有可能为器官或组织特异性运输CD4CD25抑制T细胞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.