Elucidating the Functional Role of Layilin Expression on Regulatory T cells in Skin

阐明 Layilin 表达对皮肤调节性 T 细胞的功能作用

• 批准号: 9372498
• 负责人: Michael David Rosenblum
• 金额: $ 20.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-04 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372498
• 关键词: Actins; Address; Adhesions; Antigens; Applications Grants; Autoimmune Diseases; Autoimmunity; Behavior; Biological Assay; Biology; C Type Lectin Receptors; CRISPR/Cas technology; Cell Adhesion; Cell Mobility; Cell physiology; Cells; Clinical; Coculture Techniques; Confocal Microscopy; Cutaneous; Cytoskeleton; Data; Disease; Extracellular Domain; Extracellular Matrix; Fibroblasts; Goals; Homeostasis; Human; Image; Immune; Immune Tolerance; Immune system; Impaired wound healing; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Knowledge; Literature; Measures; Mediating; Methodology; Microscopy; Molecular; Monoclonal Antibodies; Morphology; Mus; Pathway interactions; Patients; Phase; Play; Population; Production; Proteins; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Skin; Skin Cancer; Skin wound; System; Testing; Th1 Cells; Therapeutic; Tissues; Translating; Wound Healing; cell behavior; cell motility; experimental study; genome editing; innovation; interstitial; macrophage; migration; novel; overexpression; peripheral blood; protein function; stem; tool; transcriptome; transcriptome sequencing; two-photon; wound closure

Project Summary/Abstract Regulatory T cells (Tregs) play a major role in establishing and maintaining immune homeostasis. The function of these cells depends on the tissues in which they reside. We have previously shown that both murine and human skin contain a unique population of Tregs; however, the mechanisms utilized by these cells to mediate their functions in this tissue are largely unknown. Using an biased discovery approach, we identified LAYN (layilin), a novel C-type lectin receptor-like molecule, to be preferentially and highly expressed on Tregs in skin in an evolutionarily conserved manner. Layilin has been shown to interact with the extracellular matrix through its extracellular domain and with the actin cytoskeleton through its intracellular domain, suggesting that this molecule facilitates cell mobility and migration within tissues. Expression of layilin on immune cells has not been reported and the function of this protein in the context of tissue inflammation is entirely unknown. The overall goal of this proposal is to elucidate the functional role of layilin expression on Tregs in murine and human skin. We hypothesize that Tregs utilize layilin to localize and/or migrate within skin in the steady-state and/or during inflammation. In doing so, we speculate that this molecule plays a major role in Treg function in this tissue. To test this hypothesis, we have generated mice that are deficient in layilin, as well as systems to overexpress and genetically delete layilin in human Tregs. The experiments outlined herein represent a conceptually and technically innovative, systematic approach to better understand how Tregs utilize a novel molecule to regulate inflammation in skin. Our results may have implications for clinical approaches focused on functionally manipulating tissue-specific Tregs.

项目总结/摘要 调节性T细胞（Regulatory T cells，Tcells）在建立和维持免疫稳态中起主要作用。这些功能 细胞依赖于它们所在的组织。我们以前已经证明，小鼠和人类皮肤都含有一种 然而，这些细胞在该组织中介导其功能的机制是 大部分未知。使用有偏见的发现方法，我们确定了LAYN（layilin），一种新的C型凝集素受体样蛋白， 分子，以进化上保守的方式优先和高度表达在皮肤中的T细胞上。拉伊林有 已被证明通过其胞外结构域与胞外基质相互作用，并与肌动蛋白细胞骨架相互作用 通过其细胞内结构域，表明该分子促进组织内细胞的移动和迁移。 layilin在免疫细胞上的表达尚未报道，并且该蛋白在组织中的功能是 炎症完全未知。这个建议的总体目标是阐明layilin表达的功能作用 在小鼠和人类皮肤上的TcR。我们假设THBE利用layilin在皮肤内定位和/或迁移 在稳态和/或炎症期间。在这样做的过程中，我们推测这种分子在以下方面起着重要作用： Treg在这个组织中的功能。为了验证这一假设，我们已经产生了缺乏layilin的小鼠，以及 在人THEX中过表达和遗传缺失layilin的系统。本文概述的实验代表了 概念和技术创新，系统的方法，以更好地了解TTRO如何利用一种新的分子， 调节皮肤炎症。我们的研究结果可能对临床方法有意义， 操纵组织特异性TdR。