CCR4 IN SKIN LYMPHOCYTE HOMING AND IMMUNITY

趋化因子（趋化因子）是淋巴细胞从循环运输到组织损伤和炎症部位，并进入次级淋巴器官的重要介质。某些趋化因子迅速触发淋巴细胞整合素，引起内皮配体的贪婪，导致淋巴细胞在趋化因子来源附近的内皮细胞上阻滞。趋化因子分子的梯度也可以通过内皮吸引被阻滞的细胞进入周围组织。多种趋化因子在不同组织类型中表达差异，表明在特定淋巴细胞亚群向不同类型组织的差异归巢中起作用。我们已经发现（在人体系统中）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抗原CLA的皮肤归巢T细胞。相比之下，肠道（alpha4beta7+）记忆和幼稚T细胞反应较差。免疫组织化学显示，慢性炎症皮肤中参与淋巴细胞运输的小静脉具有抗tarc反应性，但不参与胃肠道固有层，提示其在循环CLA+淋巴细胞识别皮肤脉管系统中的潜在作用。与此一致的是，TARC触发CLA+（而不是alpha4beta7hi肠）记忆T细胞对ICAM-1的整合素依赖性粘附；在生理流动条件下，介导淋巴细胞在血管CLA受体e -选择素上滚动的快速整合素依赖性阻滞。结果表明，TARC及其淋巴细胞受体CCR4在淋巴细胞-内皮细胞识别和负责全身免疫和肠道免疫的淋巴细胞群的差异运输中起着重要作用。为了详细定义这一作用，我们将描述CCR4在人类特定淋巴细胞亚群中的表达和对TARC和MDC的反应（目的1）。我们将确定在小鼠中是否也观察到TARC和MDC对全身淋巴细胞和粘膜淋巴细胞的优先作用，并将询问这些反应是否依赖于ccr4（目的2）。ccr4缺陷突变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炎症皮肤中的作用（Aim 3）及其在DTH和自身免疫性牛皮癣模型中的炎症过程中的作用（Aim 4）。针对小鼠CCR4及其配体的单克隆抗体将促进这些研究（目标5）。这些研究有望确定淋巴细胞募集到全身炎症部位的关键组成部分，并可能导致皮肤（如牛皮癣）和其他炎症性疾病的新治疗方法。

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 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 (alpha4beta7+) 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 alpha4beta7hi 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.