Preserving T cell / antigen presenting cell interactions via shared L-arginine

通过共享 L-精氨酸保留 T 细胞/抗原呈递细胞相互作用

• 批准号: 10240447
• 负责人: Joseph E Qualls
• 金额: $ 19.88万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240447
• 关键词: Address; Adoptive Transfer; Amino Acids; Anabolism; Antigen-Presenting Cells; Antigens; Arginine; Attenuated; Autoimmune; Automobile Driving; Biological; CD4 Positive T Lymphocytes; Cell Communication; Cell Culture Techniques; Cell physiology; Cells; Citrulline; Communicable Diseases; Communication; Data; Drops; Environment; Enzymes; Genus Mycobacterium; Goals; Health; Hematopoietic; Host Defense; Immune; Immune response; Immunity; Immunization; In Vitro; Infection; Knowledge; L Cells; Laboratories; Lead; Lyase; Lymphocyte Function; Mediating; Metabolic Pathway; Metabolism; Mind; Mission; Modeling; Mus; Mycobacterium Infections; Names; National Institute of Allergy and Infectious Disease; Nutrient; Oranges; Pathology; Pathway interactions; Peripheral; Population; Predisposition; Process; Production; Protein Biosynthesis; Public Health; Regulation; Research; System; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Transgenic Mice; Tumor Immunity; United States National Institutes of Health; Vaccination; Virulent; amino acid metabolism; arginase; cytokine; defined contribution; extracellular; immune function; improved; intercellular communication; lymphocyte proliferation; macrophage; mycobacterial; novel therapeutics; pathogen; preservation; prevent; response; therapeutic development

PROJECT SUMMARY/ABSTRACT Amino acids are important nutrients integral to the function of T cells – key cells necessary for optimal immune activity during infection, vaccination, and anti-tumor immunity, to name a few. Harnessing amino acid metabo- lism to regulate T cell function, therefore, is an intriguing and exciting avenue of research. Still, fundamental gaps in the field include 1) understanding intercellular communication driven by amino acids, and 2) determin- ing immune cell intrinsic necessities of amino acid acquisition. The applicant’s long-term goal is to define the interplay between amino acid metabolism and basic immune responses, providing new therapeutic avenues to manipulate immune activity. The objective of this study is to 1) identify how L-arginine acquisition and utiliza- tion is regulated in T cell / antigen presenting cell interactions when L-arginine synthesis is ablated in one, or both, cell populations, and 2) determine the T cell-intrinsic necessity of L-arginine synthesis when rescuing immune-deficient mice in a mycobacteria-infection model. The applicant’s laboratory will draw on their exper- tise in defining the contribution of L-arginine metabolism during virulent and attenuated mycobacterial infection. Specifically, the applicant has generated TCR-transgenic mice specific for the dominant Ag85b mycobacterial antigen that are unable to synthesize L-arginine from L-citrulline to test how T cell L-arginine synthesis regu- lates immune function in the context of mycobacterial stimulation (in vitro) or infection (in vivo). The central hypothesis is that antigen presenting cells provide synthesized L-arginine to CD4+ T cells, enabling their ex- pansion and effector function. The applicant will test the hypothesis in two related, but independent aims. In Aim 1, the applicant will address two questions: 1) how does L-arginine synthesis in antigen presenting cells impact T cell proliferation and cytokine production, and 2) can L-arginine synthesized from L-citrulline be found within CD4+ T cells intrinsically deficient in generating L-arginine? In Aim 2, the applicant will address if T cell- intrinsic L-arginine synthesis is necessary for host immunity to mycobacteria in vivo. The proposed research is significant and is expected to lead towards a better understanding of 1) amino acid mediated regulation of lym- phocyte function and 2) communication pathways vital to T cell / antigen presenting cell interactions, potentially exposing new avenues of host-directed therapy within, and outside the realm of host defense against infection. Uncovering the impact of “immunonutrition” is expected to advance the overall missions of the NIAID and NIH by seeking fundamental knowledge to understand and prevent infectious disease, providing new directions to enhance health and reduce illness.

项目摘要/摘要 氨基酸是T细胞功能不可或缺的重要营养素 - 最佳免疫所需的关键细胞 感染，疫苗接种和抗肿瘤免疫学期间的活性仅举几例。利用氨基酸代谢 因此，调节T细胞功能的局限性是一种有趣而令人兴奋的研究途径。仍然，基本 该领域的间隙包括1）了解氨基酸的细胞间通信驱动，2）确定 - 氨基酸采集的免疫小球内在必需品。申请人的长期目标是定义 氨基酸代谢和基本免疫反应之间的相互作用，为新的治疗途径提供 操纵免疫反应性。这项研究的目的是1）确定L-精氨酸的获取和利用方式如何 当L-精氨酸合成在一个或 拯救时L-精氨酸合成所需的T细胞中的T细胞中群 分枝杆菌感染模型中的免疫缺陷小鼠。申请人的实验室将借鉴其专家 - 定义L-精氨酸代谢在有毒和减弱分枝杆菌感染过程中的贡献。 具体而言，适用的已产生了针对主要AG85B分生不理的TCR-转基因小鼠 抗原无法从L-citrulline合成L-精氨酸以测试T细胞L-精氨酸合成如何调节 在分枝杆菌刺激（体外）（体内）的情况下，LATES免疫功能。中央 假设是，抗原呈现细胞为CD4+ T细胞提供合成的L-精氨酸，从而使它们的前提 pansion和效应子函数。申请人将以两个相关但独立的目的来检验该假设。在 AIM 1，申请人将解决两个问题：1）抗原呈现细胞中的L-精氨酸合成如何 撞击T细胞增殖和细胞因子的产生，以及2）可以从L- citrulline合成L-精氨酸。 在CD4+ T细胞中本质上缺乏生成L-精氨酸？在AIM 2中，适用的如果T细胞 - 内在的L-精氨酸合成对于体内宿主对分枝杆菌的免疫是必不可少的。拟议的研究是 有意义的，预计会更好地理解1）氨基酸介导的淋巴调节 荧光细胞功能和2）对T细胞 /抗原呈现细胞相互作用至关重要的通信途径，可能有可能 在宿主防御感染的范围内和范围内暴露新的宿主定向疗法途径。 预计揭示“免疫路线”的影响将推进NIAID和NIH的整体任务 通过寻求基本知识来理解和预防传染病，向 增强健康并减少疾病。