Regulated Activation of Latent-TGFb Determines Langerhans Cell Migration

描述（由申请人提供）：朗格汉斯细胞（LC）位于皮肤表皮中--这是一个屏障部位，为朗格汉斯细胞接触皮肤病原体和肿瘤以及良性共生微生物提供了机会。本课题组和其他研究表明，LC在体内抑制对皮肤抗原的免疫反应，并可能防止对皮肤微生物的不适当反应。LC生命周期中的关键调节步骤是从表皮活化和迁移到淋巴结，在淋巴结中它们将抗原呈递给T细胞。LC迁移响应于各种炎症刺激而发生。虽然IL- 12和TNF 1被认为是LC迁移的关键介质，但在体内引入药理学水平的这些细胞因子仅诱导相对少量的LC迁移，这表明存在LC活化/迁移的其他机制。我们以前已经表明，LC的发展需要自分泌TGF-21。为了研究TGF-21在稳定状态下的作用，我们最近开发了在LC中选择性表达他莫昔芬诱导的Cre的转基因小鼠。当与TGF 21-flox小鼠交配时，他莫昔芬注射可从成年LC中消除TGF 21，并诱导几乎所有LC的自发活化和迁移。基于这一意外的发现，我们推测自分泌TGF 21信号在LC迁移中起关键作用。我们提出了一个模型，其中LC分泌的TGF-21被角质形成细胞上的整合素α v-26激活，然后直接作用于LC以维持其未成熟状态。当角质形成细胞遇到危险信号时，它们减少av 26的表面表达，从而减少LC可用的活化TGF 21的量。LC中TGF 21信号传导水平的降低促进了它们的活化和迁移。这代表了DC活化的新机制，其将对皮肤具有显著影响，并且DC生物学通常可以提供用于抑制LC活化的治疗靶标。本提案的目的是检验这一假设的有效性，并探讨其潜在机制。

DESCRIPTION (provided by applicant): Langerhans cells (LC) reside in the epidermis of the skin--a barrier site that provides LC access to cutaneous pathogens and neoplasia as well as benign commensal microorganisms. Work from our group and others indicates that LC suppress immune responses to cutaneous antigen in vivo and may prevent inappropriate responses to skin commensal microorganisms. A key regulated step in the life-cycle of LC is activation and migration from the epidermis to the lymph node where they present antigen to T cells. LC migration occurs in response to a variety of inflammatory stimuli. Though IL- 12 and TNF1 are thought to be key mediators of LC migration, introduction of pharmacological levels of these cytokines in vivo induces migration of only a relatively small number of LC suggesting that other mechanisms of LC activation/migration exist. We have previously shown that LC development requires autocrine TGF21. To examine the role of TGF21 in the steady state, we have recently developed transgenic mice that express tamoxifen inducible Cre selectively in LC. When bred to TGF21-flox mice, tamoxifen injection ablates TGF21 from adult LC and induces spontaneous activation and migration of virtually all LC. Based on this unexpected finding, we hypothesize that autocrine TGF21 signaling plays a key role in LC migration. We propose a model in which TGF21 secreted by LC is activated by integrin av26 on keratinocytes and then acts directly on LC to maintain their immature state. When keratonocytes encounter a danger signal, they decrease surface expression of av26 thereby reducing the amount of activated TGF21 available to LC. The resulting decreased levels of TGF21 signaling in LC promotes their activation and migration. This represents a novel mechanism of DC activation that would have a significant impact on skin and DC biology in general could provide a therapeutic target for the inhibition LC activation. The objective of this proposal is to test the validity of this hypothesis and explore its underlying mechanisms.