The Role of CCR4 in Skin Lymphocyte Homing and Immunity

描述(申请人提供)：趋化细胞因子(趋化因子)是 淋巴细胞从循环到部位转运的重要介体 组织损伤和炎症，并进入次级淋巴器官。一定的 趋化因子迅速触发淋巴细胞整合素，导致亲和力增加 内皮配体，导致内皮细胞上的淋巴细胞停滞 靠近趋化因子来源。趋化因子分子的梯度也可以 通过内皮细胞吸引滞留细胞进入周围组织。 各种趋化因子在不同组织类型中有不同的表达， 提示在特定淋巴细胞亚群的不同归巢中起作用 各种类型的组织。我们发现(在人类系统中) 趋化因子TARC和MDC有效吸引循环记忆T细胞 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，肠道(a4b7+)记忆和幼稚T细胞 很差。免疫组织化学显示受累小静脉呈抗TARC反应 在慢性炎症皮肤中的淋巴细胞运输中，但在 胃肠道固有层，暗示在循环中的潜在作用 Cla+淋巴细胞对皮肤血管的识别作用。与此一致，TARC 触发CLA+(但不是肠道4B7)记忆的整合素依赖的黏附 T细胞对ICAM-1的作用；并介导淋巴细胞的快速整合素依赖的停滞 生理性流动下血管CLA受体E-选择素的滚动 条件。结果表明，TARC及其淋巴细胞起着重要作用 CCR4受体在淋巴细胞-内皮细胞识别和分化中的作用 导致全身和肠道疾病的淋巴细胞群的运输 豁免权。为了详细定义这一角色，我们将在这里描述 CCR4的表达和对TARC和MDC的反应性 人的淋巴细胞(目标1)。我们将确定是否有优惠效果 系统淋巴细胞与粘膜淋巴细胞上的TARC和MDC也被观察到。 鼠标，并将询问这些反应是否依赖CCR4(目标2)。这个 获得突变的CCR4缺陷小鼠品系将使我们能够探索 该受体在靶向淋巴细胞归巢至炎症皮肤中的作用(目标3) 及其在迟发型超敏反应和自身免疫模型炎症过程中的作用 牛皮癣(目标4)。抗小鼠CCR4及其配体的单抗将 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炎症部位的成分，并可能 导致皮肤病(即牛皮癣)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.