CD1d-restricted NKT cells in microbial infection

描述(由申请者提供)：本建议书描述了一项为期5年的临床病理学学术生涯发展培训计划。这位候选人正在波士顿的哈佛医学院完成临床实验室医学的住院医师培训，现在他提议扩大他在基础免疫生物学和传染病免疫学研究方面的科学背景和技能。该计划将在赞助商、波士顿布里格姆妇女医院风湿病、免疫学和过敏科主任迈克尔·布伦纳博士的实验室提供CD1抗原呈递和T细胞功能方面的指导研究，他是CD1生物学领域公认的领导者。布伦纳博士在成功培训临床科学家方面有着出色的记录。为了能够成功地培训和完成提案中的B细胞生物学方面的工作，B细胞生物学领域公认的专家Shiv Pillai博士将担任共同导师。除了开发一个独立的项目领域外，该项目与课程作业、讲座、研讨会和职业指导的补充将促进候选人发展成为一名独立的学术研究人员。这项拟议的研究项目将研究自然杀伤T细胞(NKT)的功能，自然杀伤T细胞是一种专门的T细胞亚群，可以识别CD1d呈递的脂质和糖脂抗原。NKT细胞与宿主对微生物感染的防御密切相关，然而，对于NKT细胞在微生物感染过程中的激活机制，以及NKT细胞在产生成功的保护性免疫反应过程中与免疫系统其他细胞的相互作用，人们知之甚少。我们建议检查NKT细胞在被包裹的病原体肺炎链球菌感染过程中的作用和功能。为了探讨肺炎链球菌感染过程中NKT细胞活化的机制，我们将确定TLR介导的信号转导、细胞因子信号转导和自身抗原识别在NKT细胞对肺炎链球菌应答中的作用(目标1)。此外，我们将从肺炎链球菌中分离脂类和脂化多糖，并确定这些化合物是否可以被NKT细胞识别为CD1d呈递的同源抗原(目标2)。接下来，我们将研究NKT细胞在肺炎链球菌感染期间产生保护性抗体反应中的作用，特别是对衣壳多糖抗原的作用(目标3)。这些研究试图解决有关NKT细胞在微生物免疫中的功能的基本问题。这对寄主防御感染等疾病具有重要意义。在美国，肺炎链球菌感染是导致疾病和死亡的主要原因。拟议的研究对于了解对这种病原体的免疫很重要，并可能导致免疫保护和疫苗开发的新策略。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in Clinical Pathology. The candidate is completing residency training in clinical laboratory medicine at Harvard Medical School, Boston, and now proposes to expand his scientific background and skills in research of basic immunobiology and immunology of infectious diseases. The program will provide mentored research in the area of CD1 antigen presentation and T cell function in the laboratory of the sponsor, Dr. Michael Brenner, Chief of the Division of Rheumatology, Immunology and Allergy at Brigham and Women's Hospital, Boston, who is a recognized leader in the field of CD1 biology. Dr. Brenner has an outstanding record of successfully training clinician scientists. In order to allow successful training in and completion of the B cell biology aspect of the proposal, Dr. Shiv Pillai, a recognized expert in the field of B cell biology, will serve as co-mentor. In addition to the development of an independent project area, the complementation of the program with coursework, lectures, seminars and career mentoring will promote the candidate's development into an independent academic investigator. The proposed research project will investigate the function of Natural Killer T (NKT) cells, a specialized subset of T cells that recognizes CD1d-presented lipid and glycolipid antigens. NKT cells have been strongly implicated in host defense to microbial infection, however, little is known about both the mechanism of NKT cell activation during microbial infection and the interaction of NKT cells with other cells of the immune system during the generation of a successful protective immune response. We propose to examine the role and function of NKT cells during infection with the encapsulated pathogen Streptococcus pneumoniae. To investigate the mechanism of NKT cell activation during this infection, we will determine the role of TLR-mediated signaling, cytokine signaling and self-antigen recognition for NKT cell responses to S. pneumoniae (Aim 1). In addition, we will isolate lipids and lipidated polysaccharides from S. pneumoniae bacteria and determine whether these compounds can be recognized by NKT cells as cognate CD1d- presented antigens (Aim 2). Next, we will examine the role of NKT cells in generating a protective antibody response during S. pneumoniae infection, in particular to capsular polysaccharide antigens (Aim 3). These studies seek to address fundamental unanswered questions regarding the function of NKT cells in microbial immunity. This has significance for host defense to infection and other diseases. Infection with S. pneumoniae is a leading cause of illness and death in the United States. The proposed studies are important for understanding immunity to this pathogen and could lead to new strategies for immune protection and vaccine development.