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：
9974461
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974461
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.

项目概要 2 型辅助 T (Th2) 免疫调节体液反应，是过敏性和自身免疫性疾病的基础以及宿主免受寄生虫感染的保护，从而了解如何发育、维持。 Th2 细胞的功能和功能受到调节将有利于我们针对这些疾病的治疗方法。当遇到树突状细胞 (DC) 呈递的同源抗原时，幼稚 CD4T 细胞需要数次 Th1、Th2 和 Th17 细胞等效应细胞的分化途径，但它们如何决定分化途径 Th2 相对于其他 DC 的体内分化尚不完全清楚。异质子集并为 CD4T 细胞的分化提供两个重要线索 - 通过刺激我们之前已经证明 CD301b (Mgl2) 是由 T 细胞受体和细胞因子特异性表达的。大多数 CD11b+DC 存在于皮肤真皮和其他器官中，并且 CD301b+DCs 导致 2 型免疫后 Th2 细胞发育出现严重的选择性缺陷木瓜蛋白酶或明矾等佐剂，或感染巴西钩虫后。然而，CD301b+DCs 如何需要和/或足以诱导 Th2 分化，以及它们是否也发挥作用我们最近培育了 Mgl2-Cre 小鼠，其在外周器官 Th2 细胞中的维持作用尚不清楚。并通过使用 Mgl2-Cre 小鼠和 Mgl2-DTR 证实了 CD11b+DC 中的 Cre 重组酶活性。我们之前制作的小鼠（其中 CD301b+DC 中的白喉毒素受体表达允许它们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启动 Th2 分化所必需的，(2) 如果 CD301b+DC 足以诱导 Th2 细胞，以及 (3) 是否以及如何需要 CD301b+DC 维持皮肤中的效应和记忆Th2细胞这些方法不仅会加深我们的基础。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。