A new approach to homeostatic maintenance of dendritic epidermal T cells

树突状表皮 T 细胞稳态维持的新方法

• 批准号: 8843323
• 负责人: Yuan Zhuang
• 金额: $ 19.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843323
• 关键词: Acute; Address; Adult; Alleles; Antigens; Automobile Driving; Behavior; Biological; Cell Aging; Cell Lineage; Cell Maintenance; Cell physiology; Cells; Cessation of life; Clonality; Color; Development; Diphtheria Toxin; Dissection; Effector Cell; Epithelium; Frequencies; Gene Activation; Gene Deletion; Genes; Genetic; Genetic Recombination; Guidelines; Health; Histocompatibility Testing; Homeostasis; Immune response; Individual; Infection; Knock-in Mouse; Knowledge; Label; Life; Longevity; Lymphocyte; Maintenance; Mature T-Lymphocyte; Modeling; Mus; Natural regeneration; Neoplastic Cell Transformation; Organism; Outcome Study; Pathway interactions; Play; Population; Proliferating; Receptor Gene; Receptor Signaling; Regulatory Pathway; Reporter; Research; Rest; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Speed; Stem cells; System; T memory cell; T-Cell Receptor; T-Lymphocyte; Tamoxifen; Therapeutic; Thymus Gland; Tissues; Uterus; V(D)J Recombination; Wound Healing; aged; cell age; cell injury; chemokine; cytokine; fetal; genetic analysis; immune function; knockout gene; neglect; novel strategies; postnatal; progenitor; regenerative; response; self-renewal; tool; tumor

DESCRIPTION (provided by applicant): Homeostatic maintenance of somatic tissues typically requires replacement of damaged or aged cells by young cells generated from progenitors or somatic stem cells. However, not all tissue types are maintained in such a way. Dendritic Epidermal T Cells (DETC) are skin resident ?¿ T cells, which are exclusively derived from fetal thymus through V(D)J recombination of the T cell antigen receptor (TCR) genes but are maintained as a homogeneous population expressing a canonical ?¿TCR in the skin epithelium throughout postnatal life. DETC play important roles in epithelium barrier surveillance, tumor surveillance, and wound healing. The entire DETC population is self-sustained throughout life, yet the lifespan and regenerative behavior of individual DETC remain elusive. To facilitate genetic dissection of ?¿ T cells, our lab now produced the first ?¿ lineage specific Cre strain. Lineage specific conditional gene activation or deletion can be achieved in a temporally and spatially controlled manner through tamoxifen treatment. This newly established genetic tool provides an unprecedented opportunity for us to track and genetically manipulate DETC during postnatal life. We will use this genetic tool to explore two fundamental issues concerning homeostatic maintenance of DETC in the adult skin: 1) do DETC expand and/or regenerate uniformly during homeostatic maintenance and 2) the necessity of TCR signaling in either long-term maintenance of DETC or routine function such as wound healing. First, we will combine the inducible Cre with a multi-color fluorescent reporter to label DETC and track their clonal behavior in live mice. Second, we will use the inducible Cre system to disrupt the TCR signaling pathway through conditional gene knockout. The homogeneity of DETC TCR supports the idea that antigens play an important role in the initial selection of DETC. Whether TCR signaling is needed for long-term homeostatic maintenance of DETC is not known. The proposed study will lay the groundwork for genetic analysis of regulatory pathways underpinning homeostatic maintenance of DETC in adult life. The study of DETC also serves as an excellent model for understanding the fundamental rules of tissue maintenance in adult life, particularly in the case where tissue maintenance is independent of progenitor or somatic stem cells.

描述（由申请人提供）：体细胞组织的稳态维持通常需要由祖细胞或体细胞干细胞产生的年轻细胞替换受损或老化的细胞。然而，并不是所有的组织类型都以这种方式维持。树突状表皮T细胞（DETC）是皮肤常驻细胞吗？T细胞是通过T细胞抗原受体（TCR）基因的V(D)J重组而完全从胎儿胸腺中获得的，但作为一种表达标准？出生后皮肤上皮中TCR的变化。DETC在上皮屏障监测、肿瘤监测和伤口愈合中发挥重要作用。整个DETC种群在整个生命中都是自我维持的，但DETC个体的寿命和再生行为仍然难以捉摸。以方便基因解剖？我们的实验室现在制造出了第一个T细胞？谱系特定的Cre菌株。谱系特异性条件基因激活或缺失可以通过他莫昔芬治疗以时间和空间控制的方式实现。这种新建立的遗传工具为我们在出生后的生活中追踪和基因操纵DETC提供了前所未有的机会。我们将使用这个遗传工具来探讨关于成人皮肤DETC的稳态维持的两个基本问题：1)DETC在稳态维持过程中是否均匀地扩张和/或再生；2)TCR信号在DETC的长期维持或常规功能（如伤口愈合）中的必要性。首先，我们将把可诱导的Cre与多色荧光报告基因相结合，标记DETC并追踪其在活体小鼠中的克隆行为。其次，我们将使用诱导性Cre系统通过条件基因敲除来破坏TCR信号通路。DETC TCR的同质性支持了抗原在DETC初始选择中起重要作用的观点。TCR信号是否需要DETC的长期稳态维持尚不清楚。拟议的研究将为成人生活中DETC稳态维持的调控途径的遗传分析奠定基础。DETC的研究也为理解成人生活中组织维持的基本规则提供了一个很好的模型，特别是在组织维持独立于祖细胞或体细胞的情况下。