Induction of Th 17 immunity by different cutaneous dendritic cell populations

描述（由申请人提供）：本申请指导Alicia Mathers博士的职业和研究发展计划，她是一位免疫学训练的博士后研究员，致力于皮肤免疫学的研究项目和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。该提案将帮助Mathers博士实现她目前的目标，即过渡到独立研究者，并成为皮肤免疫学领域的领导者。为了实现她的短期过渡目标，Mathers博士将与Larregina博士一起完成当前的研究项目，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，因此本提案中详细的职业规划增强了她的免疫学基础，同时也提供了皮肤病学领域的进一步培训，以便她在皮肤免疫学研究方面具有竞争力。她的研究计划是探索由dc引起的皮肤免疫反应，这加强了她的职业规划。Mathers博士先前利用人表皮真皮外植体的离体模型进行的研究表明，皮肤迁移性dc （smiDCs）诱导CD4+ T辅助细胞（Th） 17和Th1反应共存。此外，她已经证明表皮常驻朗格汉斯细胞（LCs），而不是真皮DC (ddc)，是皮肤DC亚群，负责启动Th17免疫。因此，该提案的假设是“皮肤DC人群中观察到的th17偏置能力的差异是通过各自微环境对先天内源性危险信号的不同释放而产生的”。因此，本提案的目的是研究被称为警报的表皮危险信号，包括高迁移率组框1 （HMGB1）和ATP，是否可能负责人类和小鼠LCs的Th17偏倚功能，以及暴露于与LCs相似的Th17偏倚条件下的ddc是否会获得启动和维持Th17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将研究表皮内源性警报器HMGB1和ATP激活能够启动Th17反应的人类LCs的能力，这些LCs与Th1细胞共存。具体目标2将确定人类ddc在接受Th17偏向刺激时是否有能力启动Th17反应。特异性目的3将分析小鼠皮肤dc诱导Th17反应的能力。

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.