CCR4 IN SKIN LYMPHOCYTE HOMING AND IMMUNITY

趋化细胞因子是淋巴细胞从循环运输到组织损伤和炎症部位以及进入次级淋巴器官的重要介质。某些趋化因子快速触发淋巴细胞整联蛋白，引起与内皮配体的亲合力，导致淋巴细胞在靠近趋化因子来源的内皮细胞上的停滞。趋化因子分子的衍生物也可以吸引被抑制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，表明在特异性淋巴细胞亚群向各种组织类型的差异归巢中起作用。 我们已经发现（在人类系统中）趋化因子TARC和MDC有效地吸引循环系统性记忆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（α 4 β 7+）记忆和幼稚T细胞反应较差。 免疫组织化学显示，抗TARC反应与淋巴细胞运输在慢性炎症的皮肤，但不是在胃肠道固有层参与小静脉，这表明在循环CLA+淋巴细胞识别皮肤脉管系统的潜在作用。与此一致，TARC触发CLA+（但不是α 4 β 7 hi肠）记忆T细胞与ICAM-1的整合素依赖性粘附;并介导在生理流动条件下在血管CLA受体E-选择素上滚动的淋巴细胞的快速整合素依赖性停滞。 结果表明TARC及其淋巴细胞受体CCR 4在淋巴细胞-内皮细胞识别和淋巴细胞群体的差异运输中起着重要作用，这些淋巴细胞群体负责全身与肠道免疫。 为了详细定义这种作用，在此我们将描述人类淋巴细胞特化亚群中CCR 4的表达和对TARC和MDC的反应性（目的1）。我们将确定TARC和MDC对全身淋巴细胞与粘膜淋巴细胞的优先效应是否也在小鼠中观察到，并将询问这些反应是否是CCR 4依赖性的（目的2）。突变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（Aim 3）及其在DTH和自身免疫性银屑病模型中的炎症过程中的作用（Aim 4）。针对小鼠CCR 4及其配体的单克隆抗体将促进这些研究（目的5）。 这些研究有望确定淋巴细胞募集到全身部位炎症的关键组成部分，并可能导致皮肤（即银屑病）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.