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Regulated Activation of Latent-TGFb Determines Langerhans Cell Migration

潜在 TGFb 的调节激活决定朗格汉斯细胞迁移

基本信息

批准号：
8233827
负责人：
Daniel H Kaplan
金额：
$ 33.98万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233827
关键词：
Ablation Acute Adult Affect Antigens Benign Binding Biology Bone Marrow Breeding Cell Maturation Cell Ontogeny Chimera organism Complex Cutaneous Development Epidermis Exposure to Genetic Genetic Transcription Goals Haptens Histocompatibility Testing Immune Immune response Immune system Infectious Skin Diseases Inflammation Inflammatory Injection of therapeutic agent Integrins Interleukin-12 Langerhans cell Life Cycle Stages Lymphoid Mediator of activation protein Modeling Mucous Membrane Mus Neoplasms Organ Oropharyngeal Peptide Hydrolases Peptides Physiological Play Process Regulation Role Signal Transduction Site Skin Stimulus Surface T cell response T-Lymphocyte TNF gene Tamoxifen Testing Time Tissues Transgenic Mice Translations Ultraviolet Rays Work autocrine base cell motility cell type cytokine gastrointestinal in vivo keratinocyte langerin lymph nodes microbial microorganism migration novel paracrine pathogen prevent receptor recombinase response therapeutic target

项目摘要

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. PUBLIC HEALTH RELEVANCE: Langerhans cells (LC) are the prototypic tissue-type DC that reside in the epidermis of the skin where they are exposed to cutaneous pathogens and neoplasia as well as benign 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. Based on our novel discovery that the ablation of TGF21 in LC results in activation and migration, we hypothesize that TGF21 signaling plays a key role in regulating this process. The objective of this proposal is to test the validity of this hypothesis and explore its underlying mechanisms.

描述（由申请人提供）：朗格汉斯细胞 (LC) 存在于皮肤表皮中，这是一个屏障位点，为 LC 提供接触皮肤病原体和肿瘤以及良性共生微生物的机会。我们小组和其他人的工作表明，LC 可抑制体内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当反应。 LC 生命周期中的一个关键调控步骤是激活并从表皮迁移到淋巴结，在淋巴结中向 T 细胞呈递抗原。 LC 迁移是对多种炎症刺激的反应。尽管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仅诱导相对少量的LC迁移，表明存在LC激活/迁移的其他机制。我们之前已经表明，LC 的发育需要自分泌 TGF21。为了研究 TGF21 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型 Cre 的转基因小鼠。当与 TGF21-flox 小鼠交配时，注射他莫昔芬会消除成年 LC 中的 TGF21，并诱导几乎所有 LC 的自发激活和迁移。基于这一意外发现，我们假设自分泌 TGF21 信号在 LC 迁移中发挥关键作用。我们提出了一种模型，其中LC分泌的TGF21被角质形成细胞上的整合素av26激活，然后直接作用于LC以维持其未成熟状态。当角质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 的量。由此导致 LC 中 TGF21 信号传导水平降低，促进其激活和迁移。这代表了一种新的 DC 激活机制，将对皮肤产生重大影响，并且 DC 生物学一般可以为抑制 LC 激活提供治疗靶点。该提案的目的是测试该假设的有效性并探索其潜在机制。公共卫生相关性：朗格汉斯细胞 (LC) 是驻留在皮肤表皮中的原型组织型 DC，在那里它们暴露于皮肤病原体和肿瘤以及良性共生微生物。 LC 生命周期中的一个关键调控步骤是激活并从表皮迁移到淋巴结，在淋巴结中向 T 细胞呈递抗原。基于我们的新发现，即 LC 中 TGF21 的消除会导致激活和迁移，我们假设 TGF21 信号传导在调节这一过程中发挥关键作用。该提案的目的是测试该假设的有效性并探索其潜在机制。