Unmasking the Immunomodulatory Roles of CD7 Signaling

揭示 CD7 信号传导的免疫调节作用

• 批准号: 10637876
• 负责人: Wan-Lin Lo
• 金额: $ 53.38万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637876
• 关键词: Acute; Adaptor Signaling Protein; Address; Adoptive Transfer; Aging; Antiviral Response; Autoimmune Diseases; Binding; CD3 Antigens; CD7 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Characteristics; Chronic; Clinical; Complex; Cutaneous T-cell lymphoma; Data; Disease; Doctor of Philosophy; Epigenetic Process; Extracellular Domain; Freund' s Adjuvant; Functional disorder; Future; Goals; HIV/HCV; Human; Immunity; Impairment; In Vitro; Infection; Inflammation; Interleukin-2; Laboratories; Ligands; Link; Lymphocytic choriomeningitis virus; MHC Interaction; Major Histocompatibility Complex; Malignant Neoplasms; Mission; Modeling; Molecular; Molecular Profiling; Monitor; Mus; National Institute of Allergy and Infectious Disease; Outcome; Ovalbumin; PIK3CG gene; PTPRC gene; Pathologic; Peptide Receptor; Peptide/MHC Complex; Physiological; Production; Proliferating; Property; Proteomics; Receptor Activation; Receptor Signaling; Role; SECTM1 gene; Scaffolding Protein; Sezary Syndrome; Signal Transduction; Stimulus; T cell differentiation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Transgenic Mice; Universities; Utah; Validation; Viral; Virus Diseases; Work; acute infection; aged; autoimmune toxicity; chronic infection; cytotoxicity; design; druggable target; effector T cell; exhaust; exhaustion; experimental study; functional adaptation; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; in vivo; medical schools; multiple omics; mutant; novel; prevent; receptor; receptor function; recruit; release of sequestered calcium ion into cytoplasm; scaffold; senescence; synergism; therapeutic development; transcriptomics

PROJECT SUMMARY/ABSTRACT This NIAID R01 proposal describes the framework in which Wan-Lin Lo, Ph.D., will address the signaling properties and physiological function of CD7 in T cells in her independent laboratory at the University of Utah School of Medicine. While previous studies have treated CD7 as an inessential costimulatory molecule, the preliminary results in this proposal suggest that CD7 supports T cell receptor (TCR) signaling and effector functions: CD7 may function as a major PI3K-recruiting scaffold protein for the TCR in a ligand-independent way and as a costimulatory receptor that lowers the TCR activation threshold. Dr. Lo envisions that CD7 is a novel immunoregulatory target for the modulation of T cell function in infections, cancers, and autoimmune diseases. The overall goals of this proposal are to characterize the mechanisms used by CD7 to facilitate T cell differentiation during infection and to explore the possibility of targeting CD7 to enhance or mitigate T cell effector function. The first goal will examine the influences of CD7-involved signaling in T cells during acute and chronic viral infection at the proteomic, transcriptomic, and epigenetic levels, with the hypothesis that CD7 amplifies proximal TCR signaling, stabilizes TCR:peptide–major histocompatibility complex interactions, and enhances T cell responses to weak ligands. The second goal will define altered T cell fates in the absence of CD7 during acute and chronic viral infection to test the hypothesis that CD7-involved signaling is essential to promote antiviral T cell effector function, and that an optimal level of CD7 signaling is required to prevent T cell exhaustion due to CD7 hyperreactivity or to avoid T cell unresponsiveness due to the absence of CD7. The objective of this study is to address the current roadblocks to immunomodulatory therapies (i.e., T cell exhaustion and autoimmune toxicities). The focuses of this proposal are highly relevant to the mission of NIAID, and will enhance our understanding of the signaling mechanisms underlying T cell fate decisions during infection, especially the inherent, characteristic proteomic adaptations and epigenetic reprogramming that reinforce T cell identities. Ultimately, this work will aid the design and development of therapeutics to target CD7, and potentiate future studies to assess how CD7-modulated T cell functional adaptation may be regulated in various disease settings.

项目摘要/摘要 NIAID R01提案描述了罗万林博士将处理信令的框架 犹他大学独立实验室T细胞中CD7的特性和生理功能 医学院。虽然之前的研究将CD7视为一种不必要的共刺激分子，但 这项研究的初步结果表明，CD7支持T细胞受体(TCR)信号和效应 功能：CD7可能是TCR的主要PI3K募集支架蛋白，其功能不依赖于配体 作为一种共刺激受体，可降低TCR激活阈值。罗博士设想CD7是一部小说 在感染、癌症和自身免疫性疾病中调节T细胞功能的免疫调节靶标。 这项提案的总体目标是描述CD7用来促进T细胞的机制 感染过程中的分化，并探索靶向CD7以增强或减轻T细胞效应的可能性 功能。第一个目标是研究CD7信号在急慢性T细胞中的影响 蛋白质组、转录和表观遗传水平的病毒感染，假设CD7放大 近端TCR信号，稳定TCR：多肽-主要组织相容性复合体相互作用，并增强T 细胞对弱配体的反应。第二个目标将定义在没有CD7的情况下改变的T细胞命运 急性和慢性病毒感染，以检验CD7参与的信号对促进抗病毒至关重要的假设 T细胞效应器功能，且需要最佳水平的CD7信号来防止T细胞因 CD7高反应性或避免T细胞因缺乏CD7而无反应。这项研究的目的是 是解决目前免疫调节疗法的障碍(即T细胞耗尽和自身免疫 毒性)。这项提案的重点与NIAID的使命高度相关，并将加强我们的 了解在感染过程中决定T细胞命运的信号机制，特别是 固有的、特有的蛋白质组适应和表观遗传重新编程，加强了T细胞的特性。 最终，这项工作将有助于针对CD7的治疗药物的设计和开发，并增强未来 评估CD7调节的T细胞功能适应如何在各种疾病环境中被调节的研究。