Impact of T cell receptor signaling on memory CD8+ T cell stemness

T 细胞受体信号传导对记忆 CD8 T 细胞干性的影响

• 批准号: 10676407
• 负责人: Erik Guillen
• 金额: $ 5.27万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676407
• 关键词: Antigens; Autoimmunity; Binding; Biological Assay; CD8-Positive T-Lymphocytes; Cells; Cellular biology; Chromatin; Clonal Expansion; Data; Empathy; Epigenetic Process; Epitopes; Exhibits; Flow Cytometry; Foundations; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Health; Human; IRF4 gene; Immunize; Immunologic Memory; Immunotherapy; Infection; Listeria monocytogenes; Longevity; MHC Interaction; Maintenance; Mediating; Memory; Mentorship; Modeling; Mus; Ovum; Peptide/MHC Complex; Peptides; Phenotype; Physicians; Point Mutation; Productivity; Receptor Signaling; Reporter; Research; Role; Scientist; Signal Transduction; T cell differentiation; T cell therapy; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TCR Activation; Techniques; Testing; Training; Transgenic Organisms; Tumor Immunity; Vaccine Design; Vaccines; Variant; Work; cellular transduction; cytokine; cytotoxic; design; differential expression; experimental study; high dimensionality; imprint; improved; innovation; mouse model; neoplastic cell; overexpression; pathogen; precursor cell; prevent; programs; promoter; rational design; response; self-renewal; stem cells; stemness; transcription factor; vaccine development

ABSTRACT CD8+ T cells' unique ability to sense and kill pathogen-infected and tumor cells makes developing human vaccines designed to induce potent CD8+ T cell memory an important necessity. In this proposal, we explore the roles of T cell receptor (TCR) signaling and peptide/MHC (pMHC) stability on generating memory CD8+ T cells. Strong cognate antigen interactions induce robust primary effector responses and generate larger pools of memory CD8+ T cells. However, whether the quality of TCR signaling and pMHC interactions can imprint distinct CD8+ T cell memory programs is not well known. Prior studies state that differences in antigen stimulation do not lead to functional differences, but our preliminary data suggest that the strength and the stability of pMHC and TCR interactions do imprint functionally distinct cellular programs in resulting memory CD8+ T cells. Using high-dimensional spectral flow cytometry, transgenic TCR and fluorescent reporter mouse models, and an inducible lentiviral-based T cell gene editing approach, we will determine whether model epitopes with distinct TCR signaling qualities can imprint distinct memory cell programs. In addition, we will characterize a subset of memory CD8+ T cells that we propose are precursors to long-lived memory and test whether these cells confer improved pathogen-specific protection. I am confident that I will successfully execute the proposed research and training plans under the mentorship of Dr. Gregoire Lauvau with the support of our collaborators, Drs. Wenjun Guo and Fabien Delahaye, experts in stem cell transduction and computational genomics, respectively. Findings from our proposed study will contribute to a better understanding of memory CD8+ T cell formation and improve rational design for CD8+ T cell-based vaccines and adoptive T cell transfer immunotherapies.

摘要 CD 8 + T细胞具有独特的感知和杀死病原体感染细胞和肿瘤细胞的能力， 设计用于诱导有效的CD 8 + T细胞记忆的疫苗是重要的必需品。在本建议中，我们探讨 T细胞受体（TCR）信号传导和肽/MHC（pMHC）稳定性对产生记忆性CD 8 + T细胞的作用。 强的同源抗原相互作用诱导稳健的初级效应子应答并产生更大的抗原库。 记忆性CD 8 + T细胞。然而，TCR信号传导和pMHC相互作用的质量是否可以在不同的细胞中留下印记， CD 8 + T细胞记忆程序并不为人所知。先前的研究表明，抗原刺激的差异 不会导致功能差异，但我们的初步数据表明，pMHC的强度和稳定性 并且TCR相互作用确实在所得的记忆性CD 8 + T细胞中印记了功能上不同的细胞程序。使用 高维光谱流式细胞术、转基因TCR和荧光报告小鼠模型，以及 基于诱导型慢病毒的T细胞基因编辑方法，我们将确定模型表位是否具有不同的 TCR信号质量可以印记不同的记忆细胞程序。此外，我们将描述一个子集， 我们提出的记忆CD 8 + T细胞是长寿记忆的前体，并测试这些细胞是否赋予记忆。 提高病原体特异性保护。我有信心，我将成功地执行拟议的研究， 在Gregoire Lauvau博士的指导下，在我们的合作者Wenjun博士的支持下， Guo和Fabien Delahaye分别是干细胞转导和计算基因组学专家。结果 从我们提出的研究将有助于更好地了解记忆CD 8 + T细胞的形成和改善 基于CD 8 + T细胞的疫苗和过继性T细胞转移免疫疗法的合理设计。