TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection

感染后 CD4 T 细胞的 TCR 依赖性激活、功能分化和记忆形成

• 批准号: 10077818
• 负责人: Matthew A Williams
• 金额: $ 48.27万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-17 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077818
• 关键词: Acute; Affinity; Antigens; Automobile Driving; Bacterial Infections; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Characteristics; Clonal Expansion; Communicable Diseases; Cues; Development; Effector Cell; Frequencies; Gene Expression Profile; Generations; Genetic Transcription; Heterogeneity; IL2RA gene; Immune; Immune system; Immunity; Immunologic Memory; Immunotherapeutic agent; Infection; Lymphoid; MHC Class II Genes; Malignant Neoplasms; Measurement; Measures; Mediating; Memory; Modeling; Outcome; Play; Population; Receptor Signaling; Resolution; Role; Signal Transduction; System; T cell differentiation; T memory cell; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Therapeutic; Tissues; Vaccination; Vaccines; Virus Diseases; antigen binding; base; cytokine; design; differential expression; effector T cell; in vivo; insight; memory CD4 T lymphocyte; novel; pathogen; programs; receptor binding; response; self-renewal; therapeutic target; tool; transcription factor; transcriptome

Project Summary Because of their elevated frequency, ability to self-renew and rapid acquisition of effector function following re-activation, memory T cells have an enhanced ability to protect from secondary challenge. The generation of memory T cells is the focal point of numerous vaccine and immunotherapeutic strategies. Most (90-95%) effector T cells die after pathogen clearance, but those fated to become memory cells can be identified during the primary effector response, showing that activated T cells receive differentiation cues during the primary response to infection that influence memory fate differentiation. We have recently shown that T cell receptor (TCR) signals play a key role in driving CD4+ memory T cell differentiation. TCRs that are able to engage MHC Class II-bound antigen (pMHCII) in sustained interactions are biased towards the formation of long-lived memory, while TCRs that engage in short-lived interactions with antigen are biased towards terminal effector cell differentiation. We will build on those studies by using diverse infectious models to define aspects of the TCR-dependent activation and transcriptional program that leads to the formation of lymphoid-resident, circulating and tissue-resident CD4+ memory T cells. We pose three key questions. First, what is the role of TCR signal strength in the formation of memory T cells? We will explore the hypothesis that increasing TCR signal strength in vivo drives terminal effector T cell differentiation, while weaker TCR signal strength allows memory T cell formation. Second, what are the TCR binding parameters associated with memory T cell development? We will measure 2D affinity and bond lifetime with the application of force for TCRs at that are effector-biased or memory-biased. We will test the hypothesis that bond lifetimes will predict TCR-dependent memory differentiation. Third, what are the transcriptional programs that control memory formation? We will test the mechanistic role of molecules that are differentially expressed in memory T cell precursors during the primary effector response, including TCF-1. We anticipate that resolution of the questions posed in this study will provide a framework for determining in greater mechanistic detail how memory T cells form and identify therapeutic approaches for directly modulating CD4+ effector and memory T cell differentiation in vivo.

项目摘要 由于它们频率较高，具有自我更新和快速获得效应器功能的能力 在重新激活后，记忆T细胞具有增强的能力来保护免受二次攻击。这个 记忆T细胞的产生是众多疫苗和免疫治疗策略的重点。多数 (90%-95%)效应T细胞在病原体清除后死亡，但那些注定要成为记忆细胞的细胞可能 在初级效应器反应中被识别，表明激活的T细胞接收分化提示 在对感染的初级反应中，影响记忆命运分化。我们最近展示了 T细胞受体(TCR)信号在驱动CD4+记忆性T细胞分化中起关键作用。TCR是 能够与MHC II类结合抗原(PMHCII)进行持续相互作用的人倾向于 形成长寿记忆，而与抗原进行短暂相互作用的TCR是有偏见的 走向终末效应细胞分化。我们将在这些研究的基础上，使用不同的传染病模型 定义TCR依赖的激活和转录程序的各个方面，从而导致 淋巴驻留、循环和组织驻留的CD4+记忆T细胞。我们提出了三个关键问题。第一, TCR信号强度在记忆T细胞形成中的作用是什么？我们将探讨这样的假设 体内TCR信号强度增加促进终末效应器T细胞分化，而TCR信号减弱 力量允许记忆T细胞的形成。第二，与TCR绑定参数相关的是什么 记忆T细胞发育？我们将通过力的应用测量2D亲和力和键寿命 在这一点上，TCR是偏向效应器或偏向记忆的。我们将检验这一假设，即债券寿命将预测 依赖TCR的记忆分化。第三，控制记忆的转录程序是什么 队形？我们将测试记忆T细胞中差异表达的分子的机制作用 在主要效应器反应期间的前体，包括TCF-1。我们期待着这一解决方案 这项研究中提出的问题将提供一个框架，以便更详细地确定 记忆T细胞形成并识别直接调节CD4+效应器和记忆T的治疗方法 体内细胞分化。