The Role of Innate Immune Cell Trafficking in Th2 Differentiation

先天免疫细胞运输在 Th2 分化中的作用

• 批准号: 9302656
• 负责人: Caroline Lauren Sokol
• 金额: $ 20.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-23 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302656
• 关键词: Advisory Committees; Affect; Allergens; Allergic; Allergic Disease; Allergic inflammation; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Award; Basic Science; Basophils; Bioinformatics; Blood; CCL2 gene; CCL7 gene; CCL8 gene; CCR8 gene; Cell Differentiation process; Cell Maturation; Cells; Chronic Disease; Clinical Immunology; Complement; Cutaneous; Data; Dendritic Cells; Dermal; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Emigrations; Environment; Foundations; Funding; General Hospitals; Genomics; Goals; Grant; Helper-Inducer T-Lymphocyte; High Prevalence; Hour; Human; Hypersensitivity; IgE; Immune; Immune response; Immunity; Immunization; Immunology; In Vitro; Inflammatory; Innate Immune System; Institution; Interleukin-4; Laboratories; Leadership; Ligands; Lipopolysaccharides; Massachusetts; Mediating; Medicine; Mentors; Mentorship; Mus; Nature; Outcome; Papain; Pathway interactions; Peptide Hydrolases; Peripheral; Physicians; Population; Positioning Attribute; Postdoctoral Fellow; Process; Production; Publications; Publishing; Research; Resources; Role; SELL gene; Scientist; Shapes; Signal Transduction; Skin; Source; System; Systems Biology; T cell response; T-Lymphocyte; Techniques; Testing; Tissues; Training; Training Activity; Translational Research; Universities; Up-Regulation; Work; Writing; base; career; catalyst; cell motility; cell type; chemokine; chemokine receptor; cytokine; environmental allergen; experimental study; faculty research; in vivo; instructor; intravital microscopy; lymph nodes; medical schools; microscopic imaging; migration; mouse allergen; mouse model; multidisciplinary; novel therapeutics; prevent; receptor expression; response; responsible research conduct; selective expression; success; trafficking; transcriptome sequencing; translational research program

PROJECT SUMMARY Candidate Caroline Sokol, M.D., Ph.D., is an Assistant in Medicine in the Allergy and Clinical Immunology Unit at Massachusetts General Hospital (MGH) and an Instructor of Medicine at Harvard Medical School (HMS). She received her M.D./Ph.D. from Yale University, where she studied the mechanisms of innate immune control of Th2 differentiation in the laboratory of Dr. Ruslan Medzhitov. Her work there led to two first author Nature Immunology publications on the role of basophils in initiating the allergic immune response and Th2 differentiation. It also led to her current work in the laboratory of Dr. Andrew Luster at the Center for Immunology and Inflammatory Diseases (CIID) at MGH, where she has focused on the role of innate immune cell trafficking in the activation and control of the allergic immune response and Th2 differentiation. The short- term goals of this K08 award application resubmission are to provide training in intravital microscopy, advanced genomic techniques, including RNA-Seq, human immunology and translational research. Dr. Sokol’s long-term goal is to develop an independent translational research program studying the innate immune control of allergic disease. The experiments, training activities, and mentoring plan outlined in this proposal will successfully position Dr. Sokol for her first R01 and an independent career as a physician-scientist. Mentorship, Training Activities, and Environment Dr. Sokol will perform the work outlined in this proposal in the CIID at MGH, under the mentorship of Dr. Andrew Luster. The CIID is a state-of-the-art multidisciplinary basic science research center focused on mechanisms of immune-mediated inflammatory diseases that serves as the foundation for immunology research at MGH. Dr. Luster is an expert in the fields of cellular trafficking and chemokine research, areas that are central to this application. Additionally, Dr. Luster has an excellent track record of mentorship, having mentored over 50 post-doctoral candidates, of which 17 are currently independently-funded research faculty at academic institutions. Additionally, Dr. Sokol has organized a Training Advisory Committee consisting of Drs. Nir Hacohen, Thorsten Mempel and Arlene Sharpe. They will provide expertise and hands-on training in advanced microscopic imaging, advanced genomic techniques, human immunology and translational research. To complement the expertise of her mentors, Dr. Sokol will complete didactic courses in bioinformatics and systems biology, grant writing, leadership, translational research, and the responsible conduct of research through the Harvard Catalyst. The collaborative opportunities, intellectual environment, and resources available to Dr. Sokol are outstanding and provide her with a clear path to independent success. Research Allergic diseases are characterized by inappropriate Type-2 immune responses targeted against non-infectious environmental allergens. Despite the high prevalence of allergic diseases, very little is known about how the innate immune system recognizes allergens and initiates the allergic immune response, which has limited research into novel therapeutics. Recent research has identified a specialized population of CD301b+ dendritic cells (DCs) located in murine skin that selectively migrates into the draining lymph node (dLN) and promotes Th2 differentiation in response to allergens. However, the pathways that promote this selective migration in response to allergens are unknown. We propose first, to define the chemokine pathways involved in the migration of CD301b+ DCs to the dLN. We show in preliminary data that allergen exposure results in the production of CCR8 ligands in the skin and dLN of mice, as well as in human skin explants. Furthermore, we provide preliminary data that in addition to CCR7 signals, CCR8 is necessary for the emigration of CD301b+ DCs from the skin and subsequent Th2 differentiation, while CCR2 prevents CD301b+ DC emigration to the dLN. However, control of CD301b+ DC migration is not the only mechanism for innate control of allergic immune initiation. Although CD301b+ DCs are necessary for Th2 differentiation, they are not sufficient to induce Th2 differentiation from naïve T cells. We next propose to determine the role and identity of accessory cells in promoting Th2 differentiation. We provide preliminary data that there is a required accessory cell that provides the necessary skewing information in tandem with antigen presentation and costimulation by DCs. These accessory cells enter the dLN via a CD62L-dependent process and the entry of this cell type corresponds with the entry of a previously undescribed IL-4 producing cell that we have identified. We believe that through the control of CD301b+ DC migration and the entry of this accessory cell, that the innate immune system precisely controls the outcome of T helper cell differentiation.

项目概要 候选人 Caroline Sokol，医学博士、博士，是过敏和临床免疫学部门的医学助理 马萨诸塞州总医院 (MGH) 和哈佛医学院 (HMS) 的医学讲师。她 获得医学博士/博士学位来自耶鲁大学，她研究了先天免疫控制的机制 Ruslan Medzhitov 博士实验室的 Th2 分化。她在那里的工作为《自然》杂志带来了两位第一作者 关于嗜碱性粒细胞在启动过敏性免疫反应和 Th2 中的作用的免疫学出版物 差异化。这也导致了她目前在该中心 Andrew Luster 博士实验室的工作。 MGH 的免疫学和炎症性疾病 (CIID)，她专注于先天免疫的作用 细胞运输在过敏性免疫反应和 Th2 分化的激活和控制中的作用。短- 重新提交 K08 奖项申请的长期目标是提供活体显微镜方面的培训， 先进的基因组技术，包括 RNA 测序、人类免疫学和转化研究。索科尔博士的 长期目标是开发一个独立的转化研究项目来研究先天免疫控制 过敏性疾病。本提案中概述的实验、培训活动和指导计划将 成功为索科尔博士奠定了她的第一个 R01 地位，并成为一名医师科学家的独立职业生涯。 指导、培训活动和环境 Sokol 博士将在 MGH 的 CIID 中、在 MGH 博士的指导下执行本提案中概述的工作。 安德鲁·卢斯特. CIID是一个最先进的多学科基础科学研究中心，专注于 免疫介导的炎症性疾病的机制，作为免疫学的基础 麻省总医院的研究。 Luster 博士是细胞运输和趋化因子研究领域的专家，这些领域 是该应用程序的核心。此外，Luster 博士拥有出色的指导记录， 指导了50多名博士后候选人，其中17名目前是独立资助的研究人员 学术机构。此外，索科尔博士还组织了一个培训咨询委员会，由博士组成。 尼尔·哈科恩、托尔斯滕·曼佩尔和阿琳·夏普。他们将提供以下方面的专业知识和实践培训 先进的显微成像、先进的基因组技术、人类免疫学和转化研究。 为了补充导师的专业知识，索科尔博士将完成生物信息学和 系统生物学、资助写作、领导力、转化研究和负责任的研究行为 通过哈佛催化剂。合作机会、智力环境和资源 索科尔博士的工作非常出色，为她提供了一条通往独立成功的清晰道路。 研究 过敏性疾病的特点是针对非传染性的不适当的 2 型免疫反应 环境过敏原。尽管过敏性疾病的患病率很高，但人们对过敏性疾病是如何发生的却知之甚少。 先天免疫系统识别过敏原并启动过敏免疫反应，这限制了 研究新疗法。最近的研究发现了 CD301b+ 树突的特殊群体 位于小鼠皮肤中的细胞（DC）选择性地迁移到引流淋巴结（dLN）并促进 Th2 分化响应过敏原。然而，促进这种选择性迁移的途径 对过敏原的反应尚不清楚。我们建议首先定义参与的趋化因子途径 CD301b+ DC 迁移至 dLN。我们在初步数据中表明，过敏原暴露会导致 在小鼠皮肤和 dLN 以及人类皮肤外植体中产生 CCR8 配体。此外，我们 提供初步数据表明，除了 CCR7 信号外，CCR8 对于 CD301b+ 的迁移也是必需的 来自皮肤的 DC 和随后的 Th2 分化，而 CCR2 则阻止 CD301b+ DC 迁移到皮肤 dLN。然而，控制 CD301b+ DC 迁移并不是先天控制过敏的唯一机制。 免疫启动。尽管 CD301b+ DC 是 Th2 分化所必需的，但它们不足以 诱导幼稚 T 细胞分化为 Th2。接下来我们建议确定以下人员的角色和身份： 辅助细胞促进 Th2 分化。我们提供初步数据，表明需要 辅助细胞，与抗原呈递同时提供必要的倾斜信息和 DC 的共刺激。这些辅助细胞通过 CD62L 依赖性过程进入 dLN，并且 该细胞类型与我们已鉴定的先前未描述的 IL-4 产生细胞的条目相对应。 我们相信，通过控制 CD301b+ DC 迁移和辅助细胞的进入， 先天免疫系统精确控制 T 辅助细胞分化的结果。