TCR signal transduction in the regulation of T cell memory

TCR信号转导在T细胞记忆调节中的作用

• 批准号: 9263878
• 负责人: Emma Teixeiro
• 金额: $ 35.96万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263878
• 关键词: Adoptive Transfer; Affect; Affinity; Antigens; Biochemical; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Complex; Data; Defect; Development; Doxycycline; Event; Gene Expression Profile; Generations; Goals; Human; Immune response; Immunity; Impairment; Infection; Inflammation; Inflammatory; Knowledge; Ligands; Link; Longevity; Membrane; Memory; Modeling; Molecular Target; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Pathogenicity; Pathway interactions; Peptide Signal Sequences; Peptides; Point Mutation; Process; Public Health; Receptor Signaling; Recovery; Reporting; Research; Role; Signal Pathway; Signal Transduction; System; T cell regulation; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Transgenic Model; Transmembrane Domain; Vaccines; Work; design; experimental study; improved; innovation; insight; mouse model; mutant; neoplasm immunotherapy; novel; novel strategies; novel therapeutic intervention; pathogen; programs; public health relevance; response; secondary infection; transcription factor; tumor; vaccine efficacy

 DESCRIPTION (provided by applicant): Generation of CD8 T cell memory critically contributes to the control of intracellular pathogens and tumors. Yet how memory T cells are generated is unclear. Signals derived from the recognition of antigen by T cell receptors (TCR) and inflammation initiate the programming of memory T cells. T-bet and Eomes are two transcription factors key in this process. Thus, as T cells progressively differentiate into memory cells, low levels of T bet and increasing levels of Eomes seem to confer memory cells with the ability to live long and vigorously expand in secondary infections. While it is known that inflammation affects both T-bet and Eomes levels, it is still unclear how antigenic signals contribute to govern these regulators of memory. Our long-term goal is to understand how TCR signals regulate memory development. Our preliminary data suggest that (1) TCR signals utilize the NFkB pathway to regulate Eomes expression and thereby, memory. (2) TCR proximal events that regulate the NFkB-Eomes-memory axis are different depending on TCR signal strength. Therefore, our central hypothesis is that TCR-dependent NFkB signals regulate Eomes expression and T cell memory development. We have generated a unique murine model where a point mutation in the TCR is able to uncouple memory differentiation from effector development and proliferation in response to strong but not weak antigenic signals. We will use this model and two new mouse models that allow for T-cell restricted conditional inhibition or enhancement of NFkB signals to test our hypothesis. In this proposal we plan to determine when and how NFkB signals regulate CD8 memory (Aim 1) and to delineate the TCR-proximal signaling events required for Eomes expression and memory under both strong and weak TCR stimulation (Aim 2). This approach is innovative because it will combine studies in novel and unique murine models that for the first time directly connect TCR signals and memory development and systems that regulate the TCR-dependent and independent activity of the NFkB pathway in sophisticated adoptive transfer experiments. The proposed research is significant since it will increase our knowledge of the signaling pathways that regulate memory differentiation and it will provide an unprecedented mechanistic insight into how strong/foreign antigenic signals and weak/self-peptide signals regulate memory programming. We anticipate that the studies in this proposal will aid in the design of new therapeutic strategies to improve vaccines and tumor therapies.

 描述（由申请人提供）：CD 8 T细胞记忆的产生对细胞内病原体和肿瘤的控制至关重要。然而，记忆T细胞是如何产生的还不清楚。来自T细胞受体（TCR）识别抗原的信号和炎症启动记忆T细胞的编程。T-bet和Eomes是这一过程中的两个关键转录因子。因此，随着T细胞逐渐分化为记忆细胞， 细胞，低水平的T bet和不断增加的Eomes水平似乎赋予记忆细胞长寿和在继发感染中剧烈扩增的能力。虽然已知炎症影响T-bet和Eomes水平，但仍不清楚抗原信号如何有助于控制这些记忆调节因子。我们的长期目标是了解TCR信号如何调节记忆发育。我们的初步数据表明：（1）TCR信号利用NF κ B通路调节Eomes表达，从而调节记忆。(2)调节NFkB-Eomes-记忆轴的TCR近端事件根据TCR信号强度而不同。因此，我们的中心假设是TCR依赖性NFkB信号调节Eomes表达和T细胞记忆发育。我们已经产生了一种独特的小鼠模型，其中TCR中的点突变能够将记忆分化与效应子发育和增殖解偶联，以响应强而非弱的抗原信号。我们将使用这个模型和两个新的小鼠模型，允许T细胞限制性条件抑制或增强NF κ B信号来测试我们的假设。在该提案中，我们计划确定NFkB信号何时以及如何调节CD 8记忆（Aim 1），并描绘在强和弱TCR刺激下Eomes表达和记忆所需的TCR近端信号传导事件（Aim 2）。这种方法是创新的，因为它将联合收割机在新颖和独特的小鼠模型中的研究首次直接连接TCR信号和记忆发育以及在复杂的过继转移实验中调节NFkB途径的TCR依赖性和独立性活性的系统。这项研究意义重大，因为它将增加我们对调节记忆分化的信号通路的了解，并将为强/外来抗原信号和弱/自身肽信号如何调节记忆编程提供前所未有的机制见解。我们预计，这项提案中的研究将有助于设计新的治疗策略，以改善疫苗和肿瘤治疗。