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

描述（由申请人提供）：最近的研究表明，新发现的称为“CD4+CD25+抑制”或“调节性”T细胞群在免疫耐受或抑制异常免疫反应中起重要作用。尽管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细胞必须迁移到靶细胞存在或迁移的组织部位。这表明CD4+CD25+抑制性T细胞的迁移行为在一定程度上决定了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（如初始T细胞、记忆T细胞和效应T细胞）在体内的迁移位置仍有待确定。此外，抑制性T细胞可能产生未知的化学引诱剂来招募靶细胞。我们发现CD4+CD25+ T细胞表达许多不同的趋化因子受体，

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.