Induction of Th 17 immunity by different cutaneous dendritic cell populations

描述（由申请人提供）：本申请指导了Alicia Mathers博士的职业和研究发展计划，Alicia Mathers博士是一名免疫学培训的博士后研究员，致力于皮肤免疫学研究计划以及对参与诱导皮肤炎症和适应性免疫的树突状细胞（DC）机制的理解。该提案将有助于Mathers博士实现其当前目标，即过渡到独立研究者，以及成为皮肤免疫学领域领导者的长期目标。为了实现她过渡的短期目标，马瑟斯博士将与拉雷吉娜博士一起完成目前的研究项目，并提交数据供发表，同时还将从职业发展课程中获得培训。Mathers博士在免疫学方面有很强的背景，专注于DC生物学，因此本提案中详细介绍的职业计划增强了她的免疫学基础，同时还提供了皮肤病学领域的进一步培训，使她在皮肤免疫学研究方面具有竞争力。她的职业规划是通过她的研究计划，探索皮肤免疫反应发起的DC增强。Mathers博士利用人表皮-真皮外植体的离体模型进行的先前研究已经证明，皮肤迁移性DC（smiDC）诱导CD 4 + T辅助细胞（Th）17和Th 1应答的共存。此外，她已经证明，表皮常驻朗格汉斯细胞（LC），而不是真皮DC（DDC），是负责启动Th 17免疫的皮肤DC亚群。因此，该提议的假设是“在皮肤DC群体的Th 17偏置能力中观察到的差异是通过它们各自的微环境对先天内源性β-信号的差异释放而赋予的”。因此，本提案的目标是研究表皮危险信号（称为alarmins）（包括高迁移率族蛋白1（HMGB 1）和ATP）负责人和鼠LC的Th 17偏置功能的可能性，以及暴露于与LC相似的Th 17偏置条件下的DDC是否会获得启动和维持Th 17免疫的能力。为了验证我们的假设，我们提出了以下具体目标：具体目标1将检查表皮内源性alarmins HMGB 1和ATP激活能够启动Th 17应答的人LC的能力，与Th 1细胞共存。具体目标2将确定当用Th 17偏置刺激处理时，人DDC是否具有启动Th 17应答的能力。具体目标3将分析鼠皮肤DC诱导Th 17应答的能力。 相关性：Th 17应答是诱导对传染病的有效免疫应答所必需的。相反，Th 17细胞与皮肤炎性和自身免疫性病理的发展和复发有关。因此，更好地了解Th 17免疫是如何启动和维持的，将对合理的疫苗设计和开发皮肤自身免疫性疾病的新治疗靶点产生积极影响。

DESCRIPTION (provided by applicant): This application directs a career and research development plan for Dr. Alicia Mathers, an immunology trained post-doctoral fellow committed to a research program in cutaneous immunology and the understanding of the dendritic cell (DC) mechanism(s) involved in the induction of skin inflammation and adaptive immunity. This proposal will assist Dr. Mathers in her current goal of transitioning to an independent investigator and her long-term goal of being a leader in the field of cutaneous immunology. To obtain her short-term goal of transitioning Dr. Mathers will complete current research projects with Dr. Larregina and submit the data for publication while also obtaining training from career development courses. Dr. Mathers has a strong background in Immunology with a focus on DC biology thus the career plan detailed in this proposal enhances her Immunology base while also providing further training in the field of Dermatology so that she will be competitive in research focused on cutaneous immunology. Her career plan is enhanced by her research plan to explore cutaneous immune responses initiated by DCs. Prior investigations by Dr. Mathers utilizing an ex vivo model of human epidermal-dermal explants has demonstrated that skin migratory DCs (smiDCs) induce the co-existence of CD4+ T helper (Th) 17 and Th1 responses. Furthermore, she has demonstrated that epidermal resident Langerhans cells (LCs), and not dermal DCs (DDCs), are the cutaneous DC subset responsible for initiating Th17 immunity. Therefore the hypothesis of this proposal is that "Differences observed in the Th17-biasing capacity of cutaneous DC populations is conferred through the differential release of innate endogenous danger-signals by their respective microenvironments". Thus, the goal of this proposal is to examine the possibility that the epidermal danger signals known as alarmins, including the high mobility group box 1 (HMGB1) and ATP, are responsible for the Th17-biasing functions of both human and murine LCs, and whether DDCs exposed to similar Th17-biasing conditions as LCs will gain the capacity to initiate and sustain Th17 immunity. To test our hypothesis we propose the following specific aims: Specific aim 1 will examine the abilities of the epidermal endogenous alarmins HMGB1 and ATP to activate human LCs capable of initiating Th17 responses, co-existent with Th1 cells. Specific aim 2 will determine if human DDCs have the capacity to initiate Th17 responses when treated with Th17-biasing stimuli. Specific aim 3 will analyze the ability of murine cutaneous DCs to induce Th17 responses. Relevance: Th17 responses are necessary for the induction of efficient immune responses to infectious diseases. Conversely, Th17 cells are implicated in the development and relapse of cutaneous inflammatory and autoimmune pathologies. Therefore, a better understanding of how Th17 immunity is initiated and sustained will have a positive impact on rational vaccine design and for the development of new therapeutic targets for cutaneous autoimmune diseases.