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

描述（由申请人提供）：最近的研究表明，新鉴定的称为“CD 4 + CD 25+抑制”或“调节”T细胞的T细胞群在免疫耐受或抑制异常免疫应答中起重要作用。虽然抑制的机制在很大程度上是未知的，但抑制性T细胞需要物理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CD 4 + CD 25+抑制性T细胞的迁移行为部分地可以决定其体内抑制活性。然而，这些抑制性T细胞相对于它们的靶细胞如初始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细胞可以产生未知的化学引诱物来募集靶细胞。我们已经发现，CD 4 + CD 25 + T细胞表达许多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亚群组成。我们假设抑制性T细胞由迁移到不同免疫应答部位的异质亚群组成（例如，全身与粘膜途径;淋巴与非淋巴途径），并且抑制性T细胞的组织特异性运输能力显著有助于其体内抑制活性。为了验证这一假设，我们将首先进行全面的体外和体内运输研究的CD 4 + CD 25+抑制性T细胞，以确定趋化因子和趋化因子受体的组织特异性运输的重要性。我们接下来将设计或操纵CD 4 + CD 25+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CD 4 + CD 25+抑制性T细胞，2）下调现有的趋化因子受体，以确定在T细胞诱导的肠道炎症和移植物抗宿主病中增加或抑制CD 4 + CD 25+抑制性T细胞活性的迁移行为。这些研究有可能提供关于器官或组织特异性CD 4 + CD 25+抑制性T细胞运输及其对免疫耐受的影响的重要信息。

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.