Molecular control of CD4 T cell ability to help B cells

项目摘要/摘要： 该提案详细介绍了一项五年研究和培训计划，其科学重点是新发现的 T 细胞群，称为“外周辅助 T 细胞”(Tph)，在患者关节中显着扩增 患有类风湿性关节炎。该候选人领导了一项研究，确定并定义了这种 CD4 T 细胞亚群（Rao 等人） 等人，《自然》，2017）。 Tph 细胞具有独特的浸润发炎组织和驱动 B 细胞反应的能力 组织内。拟议研究的长期目标是了解调节信号 Tph 细胞的发育和功能，希望发现可操纵的途径 治疗上治疗自身免疫性疾病。 这里提出的具体目标利用三种互补的方法来评估 Tph 的调节 细胞。目标 1 将确定驱动人类 T 细胞分化为 Tph 细胞表型的条件。目标 2 质疑 3 个过表达的引人注目的转录调节因子对 Tph 细胞功能的控制 在 Tph 细胞中。目标 3 评估 RA 滑膜组织样本中 Tph 细胞的发育关系 其他滑膜 T 细胞群，包括滤泡辅助 T 细胞。 这项研究结合了机制研究、患者样本和尖端技术 将为候选人提供人类转化免疫学几个关键方面的新培训。的 候选人的直接职业发展目标是获得生物信息学和生物统计方面的经验 分析、转录组数据解释、原代人类细胞的基因组操作以及科学 沟通。候选人和导师都描述了具体的职业发展计划：Dr. 淋巴细胞生物学和滑膜炎症专家 Michael Brenner 医学博士和 Soumya 博士 Raychaudhuri MD 博士，生物信息学专家，利用布莱根和布莱根医学院的强大资源 妇女医院和哈佛医学院。候选人的长期职业目标是获得终身职位—— 跟踪教师职位，从事将患者样本的高维分析与 详细的机制分析以开发诊断和治疗风湿性疾病的新方法。

Project Summary/Abstract: This proposal details a five-year research and training plan with a scientific focus on a newly discovered population of T cells, termed `T peripheral helper' (Tph) cells, that is markedly expanded in the joints of patients with rheumatoid arthritis. The candidate led a study that identified and defined this CD4+ T cell subset (Rao et al, Nature, 2017). Tph cells display a unique capacity to infiltrate inflamed tissues and drive B cell responses within the tissue. The long-term objective of the proposed study is to understand signals that regulate the development and function of Tph cells in the hope of discovering pathways that can be manipulated therapeutically to treat autoimmune diseases. The specific aims proposed here utilize three complementary approaches to evaluate the regulation of Tph cells. Aim 1 will determine conditions that drive human T cell differentiation towards a Tph cell phenotype. Aim 2 interrogates the control of Tph cell function by 3 compelling transcriptional regulators that are overexpressed in Tph cells. Aim 3 evaluates the developmental relationship of Tph cells in RA synovial tissue samples with other synovial T cell populations, including T follicular helper cells. Using a combination of mechanistic studies, patient-derived samples, and cutting-edge technologies, this study will provide the candidate with new training in several key aspects of human translational immunology. The candidate's immediate career development goals are to gain experience with bioinformatic and biostatistical analyses, interpretation of transcriptomic data, genomic manipulation of primary human cells, and scientific communication. A specific career development plan is described by both the candidate and the mentors: Dr. Michael Brenner MD, an expert in lymphocyte biology and synovial inflammation, and Dr. Soumya Raychaudhuri MD PhD, an expert in bioinformatics, capitalizing on the powerful resources at Brigham and Women's Hospital and Harvard Medical School. The candidate's long-term career goal is to attain a tenure- track faculty position pursuing research that integrates high-dimensional analyses of patient samples with detailed mechanistic analyses to develop new methods to diagnose and treat rheumatic diseases.