Regulated Activation of Latent-TGFb Determines Langerhans Cell Migration

描述（由申请人提供）：朗格汉斯细胞（LC）存在于皮肤表皮，这是一个屏障部位，为LC提供了接触皮肤病原体和肿瘤以及良性共生微生物的途径。我们和其他人的研究表明，LC在体内抑制对皮肤抗原的免疫反应，并可能防止对皮肤共生微生物的不适当反应。LC生命周期中的一个关键调控步骤是活化并从表皮迁移到淋巴结，在那里它们向T细胞呈递抗原。LC迁移是对多种炎症刺激的反应。虽然IL- 12和TNF1被认为是LC迁移的关键介质，但在体内引入这些细胞因子的药理学水平只能诱导相对少量的LC迁移，这表明存在其他LC激活/迁移机制。我们之前已经证明LC的发展需要自分泌TGF21。为了研究TGF21在稳态中的作用，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TGF21-flox小鼠杂交时，注射他莫昔芬可使成年LC中的TGF21消融，并诱导几乎所有LC的自发活化和迁移。基于这一意想不到的发现，我们假设自分泌的TGF21信号在LC迁移中起关键作用。我们提出了一种模型，在该模型中，LC分泌的TGF21被角化细胞上的整合素av26激活，然后直接作用于LC以维持其未成熟状态。当角化细胞遇到危险信号时，它们会降低av26的表面表达，从而减少LC可用的活化TGF21的数量。由此导致的LC中TGF21信号水平的降低促进了它们的激活和迁移。这代表了一种新的DC激活机制，它将对皮肤和DC生物学产生重大影响，通常可以为抑制LC激活提供治疗靶点。本提案的目的是检验这一假设的有效性，并探讨其潜在的机制。

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.