Regulation of T cell egress from inflamed skin

描述（由申请人提供）：炎症和自身免疫性疾病中的淋巴细胞组织浸润是细胞进出动态平衡，结合局部增殖和凋亡的结果。尽管淋巴细胞从血液迁移到组织的机制已被广泛研究，并已被证明是局部炎症反应的关键，但T细胞从淋巴外组织迁移的机制尚不明确。虽然人们普遍认为淋巴细胞从组织中退出是一个随机过程，但我们最近发现淋巴细胞从外周组织中退出是受调节的，CD4和CD8 T细胞在非炎症条件下需要趋化因子受体CCR7的表达才能退出。CCR7和其他促进T细胞出口的“出口受体”可能会减少局部淋巴细胞的积累，从而影响免疫监视和炎症过程。由于炎性T细胞的组织出口受损会加剧局部炎症，出口受体可能成为关节炎等炎性疾病治疗的新靶点。基于我们广泛发表的和初步的数据，我们假设T细胞通过传入淋巴从炎症周围组织退出受CCR7依赖性和非依赖性机制的控制，并且CCR7和其他退出受体的相对重要性取决于局部炎症反应的性质和慢性性。在本提案中，我们将采用小鼠和大型动物模型，测试CCR7在炎症皮肤中T细胞退出中的作用，并鉴定在慢性炎症条件下介导CCR7非依赖性T细胞退出的化学引诱受体。此外，我们建议研究出口受体对旁观者和抗原特异性记忆/效应T细胞通过炎症病变再循环的调节。重要的是，使用已建立的延迟型超敏反应模型，我们将验证组织T细胞CCR7和其他出口受体的调节表达调节组织炎症的启动、维持和/或解决的假设。此外，我们预测所获得的结果将作为一个原则的证明，靶向T出口受体可以用于治疗自身免疫性和炎症性疾病，以调节炎症浸润的程度。公共卫生相关性：免疫细胞是关节炎和其他慢性炎症性疾病中组织破坏和炎症的主要细胞。我们的目标是确定免疫细胞离开炎症组织的机制。基于这些新知识，可以开发出迫使免疫细胞离开组织以阻止持续炎症和相关疼痛的治疗方法。

DESCRIPTION (provided by applicant): Lymphocytic tissue infiltrates in inflammatory and autoimmune diseases are the result of a dynamic balance of cell entry and exit, combined with localized proliferation and apoptosis. Whereas mechanisms of lymphocyte migration from the blood into tissues have been extensively studied and have proven to be key to the local inflammatory response, mechanisms responsible for T cell egress from extralymphoid tissues are only poorly defined. While it has been widely assumed that egress from tissues is a random process, we recently showed that lymphocyte exit from peripheral tissue is regulated and that CD4 and CD8 T cells require the expression of the chemokine receptor CCR7 for exit under non-inflammatory conditions. CCR7 and other "exit receptors" that promote T cell egress likely reduce localized lymphocyte accumulation, thereby affecting both immunosurveillance and inflammatory processes. As impaired tissue exit of inflammatory T cells could exacerbate local inflammation, exit receptors may serve as a novel target in the therapy of inflammatory diseases such as arthritis. Based on our extensive published and preliminary data, we hypothesize that T cell exit from inflamed peripheral tissues through the afferent lymph is controlled by both CCR7-dependent and -independent mechanisms, and that the relative importance of CCR7 and alternative exit receptors is determined by the nature and chronicity of the local inflammatory response. In this proposal, employing mouse and large animal models, we will test the role of CCR7 in T cell egress from inflamed skin as well as identify chemoattractant receptors mediating CCR7-independent T cell exit that operate under chronic inflammatory condition. Moreover, we propose to study the regulation of exit receptors on both bystander as well as antigen-specific memory/effector T cells recirculating through an inflammatory lesion. Importantly, using an established model of delayed type hypersensitivity, we will test the hypothesis that the regulated expression of tissue T cell CCR7 and other exit receptors modulate the initiation, maintenance and/or resolution of tissue inflammation. Moreover, we predict that the obtained results will serve as a proof of principle that targeting of T exit receptors can be used therapeutically to modulate the magnitude of inflammatory infiltrates in the treatment of autoimmune and inflammatory diseases. PUBLIC HEALTH RELEVANCE: Immune cells are the main cells responsible for tissue destruction and inflammation in arthritis and other chronic inflammatory diseases. Our goal is to determine the mechanisms by which immune cells leave inflamed tissues. Based on the new knowledge, therapies can be developed that force immune cells out of the tissue to stop ongoing inflammation and associated pain.