Canonical and non-canonical RasGEF pathways in T cells

摘要--项目4 T细胞对激动剂pMHC触发的TCR信号表现出显著的敏感性 承认。这些信号诱导T细胞的激活以及效应器T细胞亚群的分化以协调 对不同病原体的免疫保护，但特异性和可靠的区分的分子基础 以及对T细胞承诺的机制调节(动力学校对)还不清楚。怎么了？ 激动剂pMHC识别激活TCR信号与自身pMHC的区别 在项目1-3中，将对发生在机械水平上的相遇进行调查，重点是近端的激酶 网络，通过反馈环的校对机制，以及LAT凝聚特性。怎么了？ TCR途径将传入信号转换为激动剂pMHC识别或自身pMHC遭遇的函数 并将这些信息处理成控制T细胞激活和 差异化将在项目4中进行调查。 在项目4中，我们将检验我们的假设--在LAT信号小体下游--效应器激酶 两个Ras鸟嘌呤核苷酸交换因子(RasGEF)、SOS1和RASGRP1触发的信号调节 控制和平衡T细胞的激活和分化。具体地说，我们建议激动剂pMHC 识别触发多个驱动T细胞激活的Rasgef-Effector Kinase信号的集体输出 并以故障保险和有效的方式进行扩散。Rasgef-Effector Kinase效应器中的独特细微差别 信号进一步影响效应T细胞亚群的发育，如调节性T细胞。相比之下，我们建议 与自身pMHC的接触不会触发相同的Rasgef信号，而是将自身pMHC诱导的 将亚阈值、强直信号转化为独特的Rasgef信号，促进T细胞存活和动态平衡。在AIM 1，我们将研究正则和非正则途径中的Rasgef底物和伙伴分子。在……里面 目的2，我们将评估强直的RASGRP1-mTOR信号和T细胞的体内相关性。在目标3中，我们将确立 数字化SOS1-RAS-ERK信号在T细胞和免疫调节中的功能意义在目标4中，我们 将破译调节性T细胞和肿瘤免疫中的非典型SOS1-P38信号。 我们过去和现在在两个RAS鸟嘌呤核苷酸上的合作努力和开创性发现 交换因子(RasGEF)、SOS和RasGRP，它们对RAS/MAPK通路的典型信号，它们的 意想不到的非正则信号传递到mTOR和P38-激酶通路，创新技术形成了 在这次修订的P01更新中为项目4的四个目标奠定了基础。库里扬人、格罗夫斯人、所罗门人和 Roose-团队准备解决项目4中描述的T细胞生物学中的主要问题。 研究将提供TCR途径如何将传入信号(项目1-3)转换为有指导意义的关键结果 控制T细胞激活和分化的信号(项目4)。我们预计这些研究的结果是 将提供与人类自身免疫性疾病和癌症免疫学相关的新见解。

ABSTRACT – PROJECT 4 T cells demonstrate remarkable sensitivity to activating TCR signals triggered by agonist pMHC recognition. These signals elicit T cell activation as well as differentiation in effector T cell subsets to coordinate immune protection to different pathogens, but the molecular basis for specific and dependable discrimination and mechanistic regulation of T cell commitment (kinetic proofreading) are not understood. How the discrimination between activating TCR signals triggered by agonist pMHC recognition versus self-pMHC encounters occurs at a mechanistic level will be investigated in Projects 1-3, with focus on the proximal kinase network, proofreading mechanisms through feedback loops, and LAT condensation characteristics. How the TCR pathway converts incoming signals as a function of agonist pMHC recognition or self-pMHC encounters and processes this information into instructive Effector Kinase Signals that control T cell activation and differentiation will be investigated in Project 4. In Project 4, we will test our hypothesis that - downstream of the LAT signalosome - Effector Kinase Signals triggered by two Ras Guanine nucleotide Exchange Factors (RasGEFs), SOS1 and RasGRP1 regulate controlled and balanced T cell activation and differentiation. Specifically, we propose that agonist pMHC recognition triggers the collective output of multiple RasGEF-Effector Kinase Signals that drive T cell activation and proliferation in a failsafe and efficient manner. Unique nuances in the RasGEF-Effector Kinase effector signals further influence development into effector T cell subsets, like regulatory T cells. By contrast, we propose that contacts with self-pMHC do not trigger the same RasGEF signals, but instead, convert self-pMHC induced sub-threshold, tonic signals into unique RasGEF signals that promote T cell survival and homeostasis. In Aim 1, we will Investigate RasGEF substrates and partner molecules in canonical and non-canonical pathways. In Aim 2, we will assess tonic RasGRP1-mTOR signals and in vivo relevance in T cells. In Aim 3, we will establish the functional significance of digital SOS1-Ras-ERK signaling in T cells and regulated immunity. In Aim 4, we will decipher non-canonical SOS1-P38 signaling in regulatory T cells and tumor immunity. Our past and ongoing, collaborative efforts and seminal discoveries on two Ras Guanine nucleotide Exchange Factors (RasGEFs), SOS and RasGRP, their canonical signals to Ras/MAPK pathways, their unexpected non-canonical signals to mTOR and P38- kinase pathways, and innovative technologies form the foundation for the four Aims of Project 4 in this revised P01 renewal. The Kuriyan-, Groves-, Salomon-, and Roose- teams are poised to address the major questions in T cell biology described in Project 4. Together, these studies will provide critical results how the TCR pathway converts incoming signals (Projects 1-3) into instructive signals (Project 4) that control T cell activation and differentiation. We anticipate that results from these studies will provide novel insights relevant to human autoimmune diseases and cancer immunology.