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Regulation of Th2 differentiation by skin-resident dendritic cells

皮肤树突状细胞对 Th2 分化的调节

基本信息

批准号：
10735186
负责人：
YOSUKE KUMAMOTO
金额：
$ 47.1万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735186
关键词：
Address Allergens Allergic Disease Antigen Presentation Antigen-Presenting Cells Antigens Applications Grants Back Cell Differentiation process Cells Communicable Diseases Core Facility Cues Data Dendritic Cells Dermis Differentiation Antigens Disease Effector Cell Equipment Event Exposure to Focus Groups Goals HDAC7 histone deacetylase Helminths Helper-Inducer T-Lymphocyte Homologous Gene Hookworms Human Humoral Immunities Hypersensitivity IL2RA gene Immune Immune response Immunity Infection Inflammation Instruction Interleukin-12 Interleukin-2 Kinetics Ligation Lung Mediating Modeling Molecular Nippostrongylus Organ Papain Parasitic infection Peptide Hydrolases Peripheral Phenotype Play Regulation Role Scanning Signal Pathway Signal Transduction Skin Supporting Cell TNFRSF5 gene Testing Th2 Cells Therapeutic Up-Regulation Vaccines adaptive immunity cell type collaborative environment experimental study genetic manipulation helminth infection immunopathology imprint improved in vivo interleukin-23 mouse model novel pathogen response selective expression skin hypersensitivity vaccine development

项目摘要

Project Summary T helper type 2 (Th2) cells play a crucial role in allergies, humoral immunity and host protection against parasitic infections, but our understanding of the mechanism of their differentiation remains incomplete. Upon encountering a cognate antigen presented by dendritic cells (DCs), naive CD4T cells make a fate decision to become one of the effector cell types such as Th1, Th2, and Th17 cells. However, unlike their differentiation into Th1 or Th17 cells, in which IL-12 and IL-23 play a crucial role, respectively, the DC-derived fate instruction signal universally required for Th2 differentiation has not been identified. CD301b (Mgl2) and its human homolog CLEC10A are selectively expressed by a major subset of type 2 conventional DCs in the dermis and other peripheral organs. We previously developed mouse models in which CD301b+ DCs are depleted, enriched or genetically manipulated and demonstrated that CD301b+DCs are both necessary and sufficient for the Th2 cell differentiation upon exposure to a protease allergen papain in the skin as well as after infection with a hookworm Nippostrongylus brasiliensis. Interestingly, the depletion of CD301b+DCs results in a shift of the effector CD4T cell phonotype from Th2 to Th1 and Th17 phenotype, suggesting that CD301b+ DCs regulate the effector cell fate at the clonal level. The molecular mechanism for the Th2 fate instruction by CD301b+DCs still remains unclear, but our data indicate the requirement of cognate interactions between CD301b+DCs and antigen-specific CD4T cells. Thus, we hypothesize that CD301b+ DCs imprint the Th2 fate on CD4T cells mainly through a contact-dependent, rather than soluble, mechanisms. In this application, we aim to address the following two questions by vigorously characterizing the CD4T cell differentiation kinetics in our unique mouse models: (1) What is the CD4T cell-intrinsic, Th2-skewing signal(s) imprinted by CD301b+ DCs?; and (2) How do CD301b+ DCs instruct antigen-specific CD4T cells to become Th2 cells? Answering these questions will deepen our basic understanding of the in vivo mechanism of the initiation of a Th2 response and help us to develop a unified model that comprehensively explains the role of DC subsets in CD4T cell differentiation. Understanding such mechanism would help us to improve our strategies for treating allergic diseases and developing effective vaccines for infectious diseases.

项目摘要辅助性T细胞2型（Th 2）在过敏，体液免疫和宿主保护中起着至关重要的作用，寄生虫感染，但我们对它们的分化机制的理解仍然不完整。后当遇到由树突状细胞（DC）呈递的同源抗原时，初始CD 4 T细胞做出命运决定，成为效应细胞类型之一，如Th 1、Th 2和Th 17细胞。然而，与它们的分化不同， Th 1或Th 17细胞，其中IL-12和IL-23分别起关键作用，DC衍生的命运 Th 2分化普遍需要指令信号还没有被识别。 CD 301 b（Mgl 2）及其人同源物CLEC 10A由2型糖尿病的主要亚群选择性表达在真皮和其他外周器官中的常规DC。我们以前开发的小鼠模型，其中CD 301 b + DCs被耗尽、富集或遗传操作，并证明CD 301 b +DCs 在暴露于蛋白酶过敏原木瓜蛋白酶时，在皮肤中以及在感染了巴西日本圆线虫之后。有趣的是， CD 301 b + DC的表达导致效应CD 4 T细胞表型从Th 2向Th 1和Th 17表型转变，表明CD 301 b + DCs在克隆水平调节效应细胞的命运。的分子机制 CD 301 b +DCs对Th 2细胞命运的指示仍不清楚，但我们的数据表明， CD 301 b + DC和抗原特异性CD 4 T细胞之间的同源相互作用。因此，我们假设， CD 301 b + DC主要通过接触依赖性，而不是可溶性，机制等在本申请中，我们的目标是通过积极表征CD 4 T细胞来解决以下两个问题在我们独特的小鼠模型中的分化动力学：（1）什么是CD 4 T细胞内在的、Th 2偏斜的信号 CD 301 b + DCs？印迹;（2）CD 301 b + DCs如何指导抗原特异性CD 4 T细胞成为 Th 2细胞？对这些问题的探讨，将加深我们对肿瘤细胞凋亡的体内机制的基本认识。启动Th 2反应，并帮助我们开发一个统一的模型，全面解释的作用 CD 4 T细胞分化中的DC亚群。了解这种机制将有助于我们提高我们的治疗过敏性疾病和开发有效的传染病疫苗的策略。