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

摘要 CD8+T细胞对病原体感染和肿瘤细胞的独特感知和杀伤能力使发育中的人类 旨在诱导强大的CD8+T细胞记忆的疫苗是一项重要的必要性.在本提案中，我们探讨了 T细胞受体(TCR)信号和多肽/MHC(PMHC)稳定性在产生记忆CD8+T细胞中的作用 强烈的同源抗原相互作用诱导强大的初级效应器反应，并产生更大的池 记忆性CD8+T细胞。然而，TCR信号和pMHC相互作用的质量是否能留下鲜明的印记 CD8+T细胞的记忆程序还不是很清楚。先前的研究表明，抗原刺激的不同会 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 TCR的相互作用确实会在产生的记忆CD8+T细胞中印记功能不同的细胞程序。vbl.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 基于慢病毒诱导的T细胞基因编辑方法，我们将确定模型表位是否与 TCR信号质量可以印记不同的存储单元程序。此外，我们还将描述一个子集 我们提出的记忆CD8+T细胞是长寿记忆的前驱细胞，并测试这些细胞是否 改进了病原体特异性保护。我有信心，我将成功地执行拟议的研究和 在Gregoire Lauvau博士的指导下和我们的合作者文军博士的支持下的培训计划 郭和法比安·德拉哈耶分别是干细胞转导和计算基因组学方面的专家。发现 从我们提出的研究将有助于更好地了解记忆CD8+T细胞的形成和提高 合理设计CD8+T细胞疫苗和过继T细胞转移免疫疗法。

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.