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物质，T细胞是最佳免疫所必需的关键细胞 在感染、接种疫苗和抗肿瘤免疫期间的活动，仅举几例。利用氨基酸代谢- 因此，用来调节T细胞功能的LISM是一个有趣和令人兴奋的研究途径。尽管如此，基本的 该领域的空白包括1)了解氨基酸驱动的细胞间通讯，2)测定- ING免疫细胞获得氨基酸的内在必要性。申请者的长期目标是定义 氨基酸代谢和基本免疫反应之间的相互作用，提供了新的治疗途径 操纵免疫活动。本研究的目的是1)明确L精氨酸是如何获得和利用的。 当L-精氨酸合成被一一阻断时，TION在T细胞/抗原提呈细胞相互作用中受到调节，或者 两者，细胞群体，和2)决定了T细胞-L精氨酸合成的内在必要性 分枝杆菌感染模型中的免疫缺陷小鼠。申请人的实验室将利用他们的经验- TIE在确定L-精氨酸代谢在强毒和减毒分枝杆菌感染中的作用。 具体地说，申请者已经培育出针对主要的Ag85b分枝杆菌的TCR转基因小鼠。 不能从L-瓜氨酸合成L-精氨酸的抗原，以测试T细胞L-精氨酸合成的调节。 在分枝杆菌刺激(体外)或感染(体内)的背景下，延迟免疫功能。中环 假设抗原提呈细胞将合成的L精氨酸提供给CD_4~+T细胞，使其能够在 伸缩和效应器功能。申请者将在两个相关但独立的目标上检验这一假设。在……里面 目的1)申请人将回答两个问题：1)L精氨酸是如何在抗原提呈细胞中合成的 影响T细胞增殖和细胞因子的产生；2)是否存在由L-瓜氨酸合成的L-精氨酸 在CD_4+T细胞中天生不能产生L-精氨酸？在目标2中，申请人将解决T细胞- 体内L-精氨酸的合成是宿主对分枝杆菌免疫所必需的。拟议的研究是 具有重要意义，并有望导致更好地理解1)氨基酸介导的Lym- 细胞功能和2)对T细胞/抗原呈递细胞相互作用至关重要的通讯通路，潜在地 在宿主防御感染的领域内外揭示了宿主导向治疗的新途径。 揭示“免疫营养”的影响有望推进NIAID和NIH的总体任务 通过寻求基本知识来了解和预防传染病，提供新的方向 增进健康，减少疾病。