The Role of CCR4 in Skin Lymphocyte Homing and Immunity

描述（由申请人提供）：化学引诱细胞因子（趋化因子）是 淋巴细胞从循环运输到部位的重要介质 组织损伤和炎症，并进入次级淋巴器官。某些 趋化因子迅速触发淋巴细胞整合素，导致与 内皮配体，导致内皮细胞上的淋巴细胞停滞 靠近趋化因子的来源趋化因子分子的衍生物也可以 吸引停滞的细胞通过内皮进入周围组织。 多种趋化因子在各种组织类型中差异表达， 提示在特异性淋巴细胞亚群的差异归巢中的作用， 各种组织。我们发现（在人类系统中）， 趋化因子TARC和MDC有效地吸引循环系统记忆T 细胞，特别是表达皮肤淋巴细胞的皮肤归巢T细胞 抗原，CLA。相比之下，肠（a4 B7+）记忆和初始T细胞应答 很糟糕免疫组织化学显示抗TARC反应与小静脉参与 淋巴细胞在慢性炎症皮肤中的运输，但在 胃肠道固有层，表明在循环中的潜在作用 皮肤脉管系统的CLA+淋巴细胞识别。与此同时，TARC 触发CLA+（但不是a4 B7 hi肠）记忆的整合素依赖性粘附 T细胞的ICAM-1;并介导淋巴细胞的快速整合素依赖性停滞 在生理流量下，在血管CLA受体E-选择素上滚动 条件结果表明，TARC及其淋巴细胞的基本作用 受体CCR 4在淋巴细胞-内皮细胞识别和分化中的作用 淋巴细胞群的运输负责全身与肠道 免疫力为了详细定义这一角色，我们将在这里描述 CCR 4表达和对TARC和MDC的反应性在特化的 人淋巴细胞（Aim 1）。我们将确定， 还观察到全身淋巴细胞与粘膜淋巴细胞上的TARC和MDC， 小鼠，并将询问这些反应是否是CCR 4依赖性的（目标2）。的 突变型CCR 4缺陷小鼠系的可用性将使我们能够探索 该受体在靶向淋巴细胞归巢至发炎皮肤中的作用（目的3） 及其在DTH和自身免疫模型中的炎症过程中的作用 银屑病（目的4）。针对小鼠CCR 4及其配体的单克隆抗体将 促进这些研究（目标5）。这些研究承诺定义一个关键的 淋巴细胞募集到全身部位炎症的组分，并且可能 导致皮肤（即银屑病）和其他疾病的新治疗方法 炎症性疾病。

DESCRIPTION (provided by applicant): Chemoattractant cytokines (chemokines) are important mediators of lymphocyte trafficking from the circulation into sites of tissue damage and inflammation, and into secondary lymphoid organs. Certain chemokines rapidly trigger lymphocyte integrins, causing increased avidity with endothelial ligands, resulting in arrest of the lymphocyte on endothelial cells close to the chemokine source. Gradients of chemokine molecules can also attract arrested cells through the endothelium and into the surrounding tissue. A variety of chemokines are differentially expressed in various tissue types, suggesting a role in the differential homing of specific lymphocyte subsets to various types of tissue. We have found (in the human system) that the chemokines TARC and MDC efficiently attract circulating systemic memory T cells, especially skin-homing T cells expressing the cutaneous lymphocyte antigen, CLA. In contrast, intestinal (a4B7+) memory and naive T cells respond poorly. Immunohistochemistry reveals anti-TARC reactivity with venules involved in lymphocyte trafficking in chronically inflamed skin, but not in the gastrointestinal lamina propria, suggesting a potential role in circulating CLA+ lymphocyte recognition of skin vasculature. Consistent with this, TARC triggers integrin-dependent adhesion of CLA+ (but not a4B7hi intestinal) memory T cells to ICAM-1; and mediates rapid integrin-dependent arrest of lymphocytes rolling on the vascular CLA receptor, E-selectin, under physiologic flow conditions. The results suggest a fundamental role for TARC and its lymphocyte receptor CCR4 in lymphocyte-endothelial cell recognition and in differential trafficking of lymphocyte populations responsible for systemic vs. intestinal immunity. In order to define this role in detail, here we shall characterize CCR4 expression and responsiveness to TARC and MDC among specialized subsets of lymphocytes in man (Aim 1). We will determine if the preferential effects of TARC and MDC on systemic vs. mucosal lymphocytes are also observed in the mouse, and will ask if these responses are CCR4-dependent (Aim 2). The availability of a mutant CCR4-deficient mouse line will allow us to explore the role of this receptor in targeted lymphocyte homing to inflamed skin (Aim 3) and its role in the inflammation process in models of DTH and autoimmune psoriasis (Aim 4). Monoclonal antibodies to mouse CCR4 and its ligands will facilitate these studies (Aim 5). These studies promise to define a critical component of lymphocyte recruitment to systemic sites inflammation, and may lead to novel therapeutic approaches in cutaneous (i.e. psoriasis) and other inflammatory diseases.