Induction of Th 17 immunity by different cutaneous dendritic cell populations

描述(申请人提供)：此申请指导Alicia Mathers博士的职业生涯和研究发展计划，Alicia Mathers博士是一名免疫学博士后研究员，致力于皮肤免疫学和对树突状细胞(DC)机制(S)参与诱导皮肤炎症和适应性免疫的研究计划的理解。这项提议将有助于马瑟斯博士实现她目前过渡到一名独立研究人员的目标，以及她成为皮肤免疫学领域领导者的长期目标。为了实现过渡的短期目标，马瑟斯博士将与拉雷吉纳博士一起完成当前的研究项目，并提交数据以供发表，同时还将从职业发展课程中获得培训。Mathers博士拥有强大的免疫学背景，专注于DC生物学，因此本提案中详细介绍的职业规划增强了她的免疫学基础，同时也提供了皮肤科领域的进一步培训，使她在专注于皮肤免疫学的研究中具有竞争力。她的职业规划因探索DC引发的皮肤免疫反应的研究计划而得到加强。Mathers博士利用人表皮-真皮外植体的体外模型进行的研究表明，皮肤迁移性DC(SmiDC)可诱导CD4+T辅助细胞(Th)17和Th1反应共存。此外，她还证明了负责启动Th17免疫的皮肤DC亚群是表皮常驻朗格汉斯细胞(LCS)，而不是真皮DC(DDCS)。因此，这一建议的假设是“在皮肤DC群体中观察到的Th17偏向能力的差异是通过其各自的微环境对先天内源性危险信号的不同释放而产生的”。因此，这项建议的目的是研究被称为警报信号的表皮危险信号，包括高迁移率族蛋白1(HMGB1)和ATP，负责人和小鼠LC偏向Th17的功能的可能性，以及暴露于与LC类似的偏向Th17的条件下的DC是否将获得启动和维持Th17免疫的能力。为了验证我们的假设，我们提出了以下特定目标：特定目标1将检测表皮内源性Alarmins HMGB1和ATP激活与Th1细胞共存的人LC的能力，这些LC能够启动Th17反应。特定目标2将确定人类DDCS在受到Th17偏向刺激时是否有能力启动Th17反应。具体目标3将分析小鼠皮肤DC诱导Th17反应的能力。 相关性：Th17反应对于诱导对传染病的有效免疫反应是必要的。相反，Th17细胞与皮肤炎性和自身免疫病理的发展和复发有关。因此，更好地了解Th17免疫是如何启动和维持的，将对合理的疫苗设计和皮肤自身免疫性疾病新的治疗靶点的开发具有积极的影响。

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.