Nutrient sensing and lysosomal signaling in regulatory T cells and immune tolerance

调节性 T 细胞和免疫耐受中的营养感应和溶酶体信号传导

• 批准号: 10021398
• 负责人: Hongbo Chi
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021398
• 关键词: Alleles; Amino Acids; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Biogenesis; Biological Response Modifiers; Biology; CRISPR screen; Complex; Development; Diphtheria Toxin; Disease; Dissociation; Event; FRAP1 gene; Generations; Genetic Transcription; Goals; Homeostasis; Homologous Gene; Immune; Immune Tolerance; Immune response; Immunology; Impairment; Inflammatory; Licensing; Link; Lymphoid; Lysosomes; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Monomeric GTP-Binding Proteins; Mus; Nutrient; Prevention; Program Description; Regulation; Regulatory T-Lymphocyte; Role; Shapes; Signal Transduction; Symptoms; System; T-Cell Activation; T-Cell Receptor; Tamoxifen; Testing; Tissues; Translating; Tumor Immunity; Work; adaptive immunity; checkpoint inhibition; detection of nutrient; genome wide screen; genome-wide; immune function; immunoregulation; in vivo; inhibitor/antagonist; innovation; interest; neoplasm immunotherapy; novel; phosphoproteomics; prevent; programs; response; tumor; tumor microenvironment

Program Description/Abstract Regulatory T cells (Tregs) are central mediators of immune tolerance, but can also be a major hurdle to tumor immunity and immunotherapy. Tregs respond to TCR stimulation in the periphery and develop into activated Tregs (aTregs), whose function is important for tissue homeostasis in non-lymphoid organs and immune regulation in the tumor microenvironment. In addition to TCRs, microenvironment-derived signals, especially nutrients, have emerged as important regulators of T cell activation and differentiation, although the functional importance of nutrients in Tregs and whether and how they signal are unclear. We have a long-standing interest in understanding mTORC1 signaling in adaptive immunity and Treg biology. Our previous work has centered upon understanding the immune functions of mTORC1. How upstream signals regulate mTORC1 to shape Treg activation programs and tissue and tumor-specific responses remain poorly understood and will be the focus of this renewal application. To this end, we performed an unbiased, genome-wide screen for regulators of mTORC1 in Tregs, and identified the small G proteins RagA and Rheb1 among the top-ranking positive regulators of mTORC1 activity. Treg-specific deletion of RagA led to mild TH1-associated autoimmune responses, while loss of both RagA and the partially-redundant RagB resulted in the development of a fatal, Scurfy-like inflammatory disorder. Mechanistically, we found that RagA/B linked amino acids to mTORC1 activation and the generation of aTregs. Furthermore, we identified the functional importance of Rheb1 and its homolog Rheb2 in aTreg generation, and the interplay of RagA/B with Rheb and lysosomal signaling. We hypothesize that amino acids signal via RagA/B and interplay with Rheb and lysosomal signaling to license mTORC1 activation for functional programming of aTreg generation and suppressive activity. Aim 1. Establish the effects and mechanisms of RagA/B signaling in aTreg generation and function. Aim 2. Identify the integration of amino acid signals by TSC–Rheb and RagA/B in Tregs. Aim 3. Define lysosomal signaling and reconstruct mTORC1 signaling circuits in Tregs. We predict our studies will establish a new paradigm in Treg biology and mechanisms of mTORC1 regulation, with the potential to translate into innovative strategies to target cancer and other diseases.

程序描述/摘要 调节性T细胞是免疫耐受的中心介质，但也可能是肿瘤的主要障碍 免疫和免疫疗法。Tregs在外周对TCR刺激做出反应并发育为激活 Tregs(ATregs)，其对非淋巴器官和免疫中的组织动态平衡具有重要作用 肿瘤微环境的调控。除了TCR，微环境派生的信号，特别是 营养物质已成为T细胞活化和分化的重要调节因素，尽管其功能 营养物质在Tregs中的重要性以及它们是否和如何发出信号尚不清楚。我们有着长期的利益 了解适应性免疫和Treg生物学中的mTORC1信号。我们之前的工作集中在 在了解mTORC1的免疫功能的基础上。上游信号如何调节mTORC1的形状 Treg激活程序以及组织和肿瘤特异性反应仍然知之甚少，将是 此续订申请的焦点。为此，我们进行了一次公正的、全基因组范围的筛选，以调节 在Tregs中发现mTORc1，并鉴定出最高阳性中的小G蛋白raga和Rheb1 MTORC1活性的调节者。Treg特异性RAGA缺失导致轻度TH1相关自身免疫 反应，虽然RAGA和部分冗余的RagB的丢失导致了致命的， 皮屑样炎性疾病。从机制上讲，我们发现RAGA/B将氨基酸与mTORC1连接起来 激活和生成aTregs。此外，我们确定了Rheb1的功能重要性和它的 ATREG生成中的Rheb2同源基因，RAGA/B与Rheb和溶酶体信号的相互作用。我们 假设氨基酸通过RAGA/B传递信号，并与Rheb和溶酶体信号相互作用以 许可用于ATREG生成和抑制活动的函数式编程的mTORC1激活。 目的1.探讨RAGA/B信号在ATREG生成和功能中的作用及机制。目标2. 用TSC-Rheb和RAGA/B鉴定Tregs中氨基酸信号的整合。目标3.定义溶酶体 并在Tregs中重建mTORC1信号通路。我们预测我们的研究将建立一个新的 Treg生物学中的范式和mTORC1调节机制，具有转化为创新的潜力 针对癌症和其他疾病的战略。