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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：
10225455
负责人：
YOSUKE KUMAMOTO
金额：
$ 39.75万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
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 2023-06-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225455
关键词：
Ablation Address Adjuvant Allergens Allergic Disease Antigen Presentation Antigens Applications Grants Asthma Atopic Dermatitis Autoimmune Diseases C-Type Lectins Cell Differentiation process Cells Cues Cytokine Signaling Defect Dendritic Cells Dermal Dermatitis Dermis Development Differentiation Antigens Diphtheria Toxin Disease Effector Cell Enterobacteria phage P1 Cre recombinase Experimental Models Exposure to Family Food Hypersensitivity Genes Goals Hookworms Host Defense Humoral Immunities Hypersensitivity ITGAM gene Immunity Immunization Infection Interleukin-1 Interleukin-6 Langerhans cell Maintenance Mediating Memory Modeling Mus Nippostrongylus Organ Papain Parasitic infection Peptide Hydrolases Peripheral Phase Play Production Proteins Regulation Reporting Role Skin Supporting Cell T-Cell Activation T-Cell Receptor T-Lymphocyte Subsets Th2 Cells Therapeutic Tissues Vaccines adaptive immunity aluminum sulfate cytokine diphtheria toxin receptor experimental study helminth infection improved in vivo mouse model pathogen receptor expression recruit response

项目摘要

Project Summary T helper type 2 (Th2) immunity regulates humoral responses and underlies allergic and autoimmune diseases as well as host protection against parasitic infections. Thus, understanding how development, maintenance and function of Th2 cells are regulated would benefit our therapeutic approaches against these diseases. Upon encounter with a cognate antigen presented by dendritic cells (DCs), naive CD4T cells take several differentiation paths to effector cells such as Th1, Th2, and Th17 cells, but how they decide on the path to Th2 differentiation over the other in vivo is incompletely understood. DCs in vivo consist of highly heterogeneous subsets and provide two important cues for differentiation of CD4T cells – stimulation through the T cell receptor and cytokines. We have shown previously that CD301b (Mgl2) is specifically expressed by a majority of CD11b+DCs in the dermis of the skin as well as in other organs, and that depletion of CD301b+DCs results in a severe and selective defect in developing Th2 cells upon immunization with type 2 adjuvants such as papain or alum, or after the infection with a hookworm Nippostrongylus brasiliensis. However, how CD301b+DCs are required and/or sufficient for inducing Th2 differentiation and if they also play a role in maintaining Th2 cells in the peripheral organ are unclear. We recently generated Mgl2-Cre mouse and confirmed Cre recombinase activity in CD11b+DCs. By using the Mgl2-Cre mouse and the Mgl2-DTR mouse that we previously made (in which diphtheria toxin receptor expression in CD301b+DCs allows their specific ablation by injecting diphtheria toxin), in this proposal, we will examine (1) if direct antigen presentation and cytokine production by CD301b+DCs are required for priming Th2 differentiation, (2) if CD301b+DCs are sufficient for inducing Th2 cells, and (3) if and how CD301b+DCs are required for the maintenance of effector and memory Th2 cells in the skin. These approaches will not only deepen our basic understanding of the in vivo mechanism of Th2 regulation, but also help us to improve our strategies for treating allergic diseases or developing effective vaccines.

项目摘要辅助性T细胞2型（Th2）免疫调节体液应答，并成为过敏性和自身免疫性疾病的基础以及保护宿主免受寄生虫感染。因此，了解如何开发、维护 Th 2细胞的功能得到调节将有利于我们针对这些疾病的治疗方法。在遇到由树突状细胞（DC）呈递的同源抗原时，初始CD4T细胞需要几个周期， Th1、Th2和Th17细胞等效应细胞的分化途径，但它们如何决定向 Th2在体内相对于另一种的分化还不完全清楚。体内的DC由高度异质性亚群，并提供了两个重要的线索分化的CD4T细胞-刺激通过 T细胞受体和细胞因子。我们以前已经证明，CD301b（Mgl2）是特异性表达，大多数CD11b + DCs在皮肤真皮以及其他器官中， CD301b + DCs在2型免疫后导致Th2细胞发育严重和选择性缺陷佐剂如木瓜蛋白酶或明矾，或在用巴西日本圆线虫感染之后。然而，如何CD301b + DC是必需的和/或足够的诱导Th2分化，以及它们是否也发挥作用，维持外周器官中Th2细胞的作用尚不清楚。我们最近培育了Mgl2-Cre小鼠，并证实了Cre重组酶在CD11b + DC中的活性。通过使用Mgl2-Cre小鼠和Mgl2-DTR 我们先前制造的小鼠（其中CD301b + DC中的白喉毒素受体表达允许其通过注射白喉毒素进行特异性消融），在本提案中，我们将检查（1）是否直接抗原 CD301b + DC的呈递和细胞因子产生是引发Th2分化所必需的，（2）如果 CD301b + DCs足以诱导Th2细胞，以及（3）CD301b + DCs是否以及如何被需要用于Th2细胞，维持皮肤中的效应和记忆Th2细胞。这些方法不仅将深化我们的基本了解Th2调节的体内机制，也有助于我们改进我们的策略，治疗过敏性疾病或开发有效的疫苗。