Cis-interaction mediated CD28 costimulation

顺式相互作用介导的 CD28 共刺激

• 批准号: 10371732
• 负责人: Yunlong Zhao
• 金额: $ 12.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371732
• 关键词: Ablation; Address; Affect; Antigen-Presenting Cells; Ants; Award; Binding; Biological Assay; CD28 gene; California; Career Mobility; Cell Communication; Cells; Chronic Disease; Communicable Diseases; Cytomegalovirus Infections; Data; Development Plans; Dimensions; Dissection; Ensure; Environment; Equilibrium; Fluorescence Resonance Energy Transfer; Foundations; Goals; Health; Human; Immune; Immune response; Immunologic Receptors; Immunotherapy; In Vitro; Infection; Interleukin-2; Investigation; Knowledge; Lead; Life; Ligands; Liposomes; Malignant Neoplasms; Measures; Mediating; Membrane; Mentorship; Microscopy; Modeling; Molecular; Murid herpesvirus 1; Mus; Mutagenesis; Oncogenic Viruses; PTPRC gene; Paper; Pathway interactions; Peripheral; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Positioning Attribute; Production; Proteins; Publishing; Receptor Activation; Receptor Signaling; Research; Research Personnel; Research Training; Resolution; Resource Development; Role; Series; Signal Pathway; Signal Transduction; Solid; System; T cell regulation; T cell therapy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; Training; Universities; Viral; Virus; Virus Diseases; Western Blotting; antigen-specific T cells; base; career; career development; cytokine; effector T cell; experimental study; immune checkpoint blockade; improved; in vivo; innovation; insight; neoplastic cell; novel; overexpression; post-doctoral training; receptor; reconstitution; recruit; success; tool; tumor

Project Summary Engagement of CD28 provides a critical costimulatory signal for T cell activation. Absence of adequate CD28 costimulation is a common feature of dysfunctional T cells in cancer and viral infections. However, although augmentation of CD28 signaling is well known to be essential for restoring dysfunctional T cells protective immune responses upon immune checkpoint blockade treatment, it is unclear how CD28 in those T cells is activated in the absence of corresponding ligands on cancer and virus-infected cells, indicating the limited mechanistic understanding of the B7:CD28 pathway. My preliminary data have suggested a novel mechanism of CD28 activation by B7 on the same T cell (cis-B7:CD28 interactions), different from the known CD28 engagement by B7 on antigen-presenting cells (trans-B7:CD28 interactions). This finding has begun to reveal a unique avenue to trigger CD28 signaling in effector T cells for vigorous anti-tumor and ant-virus immune responses. Based on this finding, the objective of this K99/R00 application is to understand the function and mechanism of cis-B7:CD28 interaction and leverage cis-activation of CD28 to enhance the activity of T cells against cancer and infection. To this end, I propose the following aims: Aim 1: Establish a role of B7:CD28 cis- interactions in regulating T cells activity. Aim 2: Dissect the molecular mechanism through which CD28 is activated by B7 ligands in cis. Aim 3: Identify the function of cis-B7:CD28 interaction in T cell immune response against tumor and viral infection. These three aims will allow me to perform a comprehensive investigation on cis-B7:CD28 interactions and the knowledge gained from this study will likely provide valuable therapeutic implications in CD28 targeted T cell therapy. I have a strong background in studying cis-interactions and their functions in regulating T cell activity, which is evidenced by publishing two impactful papers during my postdoctoral training. Importantly, I have established a series of unique and robust approaches to convincingly decouple cis- and trans-interactions in coreceptors signaling. This has been the solid foundation of my proposed experiments. Moreover, my mentorship committee and I have developed an individualized research training and career development plan, which helps me obtain additional skillsets and expertise and ultimately ensures my success in seeking an independent investigator position. University of California, San Diego provides the best possible environment for my K99 research, including world-leading research, cutting-edge facilities and extensive career development resources. Overall, this K99/R00 award will fulfill my career goal to understand the function and mechanism of costimulatory receptor signaling in regulation of T cell activity and promote my career transition into an independent investigator.

项目摘要 CD 28的结合为T细胞活化提供了关键的共刺激信号。缺乏足够的CD 28 共刺激是癌症和病毒感染中功能失调的T细胞的共同特征。不过虽然 众所周知，CD 28信号传导的增强对于恢复功能失调的T细胞保护性至关重要。 免疫检查点阻断治疗后的免疫应答，目前尚不清楚这些T细胞中的CD 28是如何被激活的。 在癌症和病毒感染的细胞上缺乏相应配体的情况下激活，表明有限的 对B7：CD 28通路的机制理解。我的初步数据显示 B7在相同T细胞上激活CD 28（顺式-B7：CD 28相互作用），不同于已知的CD 28 B7与抗原呈递细胞的相互作用（trans-B7：CD 28相互作用）。这一发现已经开始揭示一个 在效应T细胞中触发CD 28信号传导的独特途径，用于强有力的抗肿瘤和抗病毒免疫 应答基于这一发现，本K99/R 00应用程序的目标是了解其功能， 顺式-B7：CD 28相互作用的机制，并利用CD 28的顺式激活来增强T细胞的活性 对抗癌症和感染为此，我提出了以下目标：目标1：建立B7：CD 28顺式- 调节T细胞活性的相互作用。目的2：探讨CD 28在肿瘤细胞中表达的分子机制。 由B7顺式配体激活。目的3：研究顺式B7：CD 28相互作用在T细胞免疫应答中的作用 抗肿瘤和病毒感染。这三个目标将使我能够进行全面的调查， 顺式-B7：CD 28相互作用和从本研究中获得的知识可能会提供有价值的治疗 在CD 28靶向T细胞治疗中的意义。我在研究顺式相互作用及其 在调节T细胞活性方面发挥作用，这一点在我的研究期间发表了两篇有影响力的论文 博士后培训。重要的是，我已经建立了一系列独特而强大的方法， 在辅助受体信号传导中解耦顺式和反式相互作用。这是我提出的坚实基础。 实验此外，我的导师委员会和我制定了个性化的研究培训， 职业发展计划，帮助我获得额外的技能和专业知识，并最终确保我的 成功寻求独立调查员职位。加州大学圣地亚哥分校提供最好的 我的K99研究可能的环境，包括世界领先的研究，尖端的设施， 丰富的职业发展资源。总的来说，这个K99/R 00奖项将实现我的职业目标， 共刺激受体信号在调节T细胞活性和促进T细胞增殖中的作用及机制 职业转型为独立调查员