TCR signal transduction in the regulation of T cell memory

 描述(申请人提供)：CD8 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。T细胞受体(TCR)识别抗原和炎症产生的信号启动记忆T细胞的编程。T-bet和eome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、低水平的T蛋白和高水平的eome似乎赋予记忆细胞在继发感染中活得更长和旺盛扩张的能力。虽然已知炎症同时影响T-bet和eome水平，但仍不清楚抗原信号如何影响这些记忆调节因子。我们的长期目标是了解TCR信号是如何调节记忆发育的。我们的初步数据表明：(1)TCR信号利用NFkB途径调节Eome的表达，从而调节记忆。(2)调节NFkB-Eome-Memory轴的TCR近端事件随TCR信号强度的不同而不同。因此，我们的中心假设是依赖于TCR的NFkB信号调节Eome的表达和T细胞记忆的发育。我们已经建立了一个独特的小鼠模型，在该模型中，TCR中的一个点突变能够将记忆分化与效应器的发育和增殖分开，以响应强而不是弱的抗原信号。我们将使用这个模型和两个新的小鼠模型来验证我们的假设，这两个模型允许T细胞限制条件抑制或增强NFkB信号。在这项提案中，我们计划确定NFkB信号何时以及如何调节CD8记忆(目标1)，并描绘在强TCR刺激和弱TCR刺激下Eome表达和记忆所需的TCR近端信号事件(目标2)。这种方法是创新的，因为它将结合对新颖和独特的小鼠模型的研究，这些模型首次将TCR信号与记忆发育直接联系起来，以及在复杂的过继转移实验中调节NFkB途径的TCR依赖和独立活动的系统。这项拟议的研究具有重要意义，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/自肽信号如何调节记忆编程提供前所未有的机制洞察。我们预计，这项提案中的研究将有助于设计新的治疗策略，以改进疫苗和肿瘤治疗。

 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.