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 由于它们的频率升高，自我更新能力和效应函数的快速获取 重新激活后，记忆T细胞具有保护次要挑战的增强能力。这 记忆T细胞的产生是众多疫苗和免疫治疗策略的焦点。最多 （90-95％）效应T细胞在病原体清除后死亡，但是那些被命名为记忆细胞的人可能是 在主要效应子响应期间鉴定出来，表明活化的T细胞获得分化线索 在影响记忆命运分化的主要反应期间。我们最近显示了 T细胞受体（TCR）信号在驱动CD4+记忆T细胞分化中起关键作用。 TCR是 能够使MHC II类结合的抗原（PMHCII）参与持续相互作用 长寿记忆的形成，而与抗原短暂相互作用的TCR有偏见 朝向末端效应细胞分化。我们将通过使用多种传染性模型来建立这些研究 定义TCR依赖性激活和转录程序的各个方面，该程序导致形成 淋巴样，循环和组织居民CD4+记忆T细胞。我们提出三个关键问题。第一的， TCR信号强度在记忆T细胞形成中的作用是什么？我们将探讨以下假设 体内TCR信号强度的提高驱动末端效应子T细胞分化，而TCR信号较弱 强度允许记忆T细胞形成。其次，与什么相关的TCR结合参数 记忆T细胞开发？我们将通过使用力量来测量2D亲和力和债券寿命 TCR在效应子偏置或记忆偏置。我们将测试债券寿命将预测的假设 TCR依赖性内存分化。第三，控制内存的转录程序是什么 编队？我们将测试在记忆T细胞中差异表达的分子的机械作用 主要效应子响应期间的前体，包括TCF-1。我们预计该解决方案 本研究中提出的问题将提供一个框架，以确定更大的机械细节 记忆T细胞形成并确定直接调节CD4+效应器和存储t的治疗方法 体内细胞分化。