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.

项目总结/摘要 氨基酸是T细胞功能不可或缺的重要营养素-最佳免疫所必需的关键细胞 在感染、疫苗接种和抗肿瘤免疫期间的活性，仅举几例。利用氨基酸代谢 因此，lism调节T细胞功能是一个有趣和令人兴奋的研究途径。尽管如此， 该领域的差距包括1）理解由氨基酸驱动的细胞间通讯，和2）确定 免疫细胞获得氨基酸的内在必要性。申请人的长期目标是确定 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， 操纵免疫活性本研究的目的是1）确定L-精氨酸的获得和利用， 当L-精氨酸合成在一个T细胞/抗原呈递细胞相互作用中被消除时， 细胞群体，和2）确定T细胞在拯救时L-精氨酸合成的内在必要性 分枝杆菌感染模型中免疫缺陷小鼠。申请人的实验室将利用他们的经验， 在确定L-精氨酸代谢的贡献在强毒和减毒分枝杆菌感染。 具体地，申请人已经产生了对优势Ag 85 b分枝杆菌特异性的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-精氨酸合成调节是如何进行的。 在分枝杆菌刺激（体外）或感染（体内）的情况下，增强免疫功能。中央 假设是抗原呈递细胞向CD 4 + T细胞提供合成的L-精氨酸，使它们的前 扩展和效应器功能。申请人将在两个相关但独立的目标中检验假设。在 目的1，申请人将解决两个问题：1）L-精氨酸如何在抗原呈递细胞中合成 影响T细胞增殖和细胞因子产生，和2）是否可以发现由L-瓜氨酸合成L-精氨酸 在CD 4 + T细胞内在缺陷产生L-精氨酸？在目标2中，申请人将说明T细胞是否- 内源性L-精氨酸合成是宿主体内对分枝杆菌免疫所必需的。拟议的研究是 显著的，并预期导致更好地理解1）氨基酸介导的LYM-1的调节， 吞噬细胞功能和2）对T细胞/抗原呈递细胞相互作用至关重要的通讯途径，可能 揭示了宿主防御感染领域内外的宿主导向治疗的新途径。 揭示“免疫球蛋白”的影响有望推进NIAID和NIH的整体使命 通过寻求了解和预防传染病的基本知识，为 增进健康，减少疾病。