Cis-interaction mediated CD28 costimulation

顺式相互作用介导的 CD28 共刺激

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 CD28 的参与为 T 细胞激活提供了关键的共刺激信号。缺乏足够的 CD28 共刺激是癌症和病毒感染中功能失调的 T 细胞的一个共同特征。然而，尽管众所周知，CD28 信号传导的增强对于恢复功能失调的 T 细胞保护至关重要。免疫检查点阻断治疗后的免疫反应，目前尚不清楚这些 T 细胞中的 CD28 是如何变化的在癌症和病毒感染细胞上缺乏相应配体的情况下被激活，表明有限的 B7:CD28 通路的机制理解。我的初步数据表明了一种新颖的机制 B7 在同一 T 细胞上激活 CD28（顺式 B7:CD28 相互作用），与已知的 CD28 不同 B7 与抗原呈递细胞的结合（反式 B7:CD28 相互作用）。这一发现已经开始揭示出在效应 T 细胞中触发 CD28 信号传导以实现强有力的抗肿瘤和抗病毒免疫的独特途径回应。基于这一发现，此 K99/R00 应用程序的目标是了解其功能和 cis-B7:CD28相互作用机制并利用CD28的顺式激活增强T细胞的活性对抗癌症和感染。为此，我提出以下目标：目标 1：建立 B7:CD28 cis- 的作用调节 T 细胞活性的相互作用。目标 2：剖析 CD28 发挥作用的分子机制由 B7 顺式配体激活。目标 3：确定 cis-B7:CD28 相互作用在 T 细胞免疫反应中的功能对抗肿瘤和病毒感染。这三个目标将使我能够对 cis-B7:CD28 相互作用以及从本研究中获得的知识可能会提供有价值的治疗 CD28 靶向 T 细胞治疗的影响。我在顺式相互作用及其相关研究方面拥有深厚的背景调节 T 细胞活性的功能，这一点通过我在我期间发表的两篇有影响力的论文得到了证明博士后培训。重要的是，我建立了一系列独特而强大的方法来令人信服地解耦共受体信号传导中的顺式和反式相互作用。这是我的提议的坚实基础实验。此外，我和我的导师委员会制定了个性化的研究培训和职业发展计划，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、尖端的设施和丰富的职业发展资源。总体而言，这个 K99/R00 奖项将实现我的职业目标共刺激受体信号调节T细胞活性及促进免疫功能的作用及机制职业转变为独立调查员。