TSC1-mTOR signaling and T cell tolerance

描述（由申请人提供）：T细胞耐受性不仅在预防自身免疫性疾病中至关重要，而且有助于肿瘤耐受性。T细胞无能和调节性T细胞（Treg）是外周T细胞耐受的两种主要形式。然而，控制T细胞无反应性和Treg的具体机制仍然没有得到很好的理解。几十年来，雷帕霉素一直被用作免疫抑制剂。它的靶点，雷帕霉素的哺乳动物靶点（mTOR），是一种丝氨酸苏氨酸激酶，通过调节营养摄取、转录、翻译、自噬和细胞存活在多种细胞过程中发挥关键作用。mTOR形成两种信号传导复合物（mTORC 1和mTORC 2），其具有不同的信号传导特性和对雷帕霉素的敏感性。最近的证据已经确定mTOR是效应T细胞分化、T细胞无反应性、诱导型调节性T细胞分化和记忆T细胞对病毒病原体应答的关键调节因子。然而，导致T细胞中mTOR活化的途径以及严格控制mTOR活性的重要性仍然知之甚少。该提案的目的是提高对mTOR信号传导的理解，以及肿瘤抑制结节复合物1（TSC 1）作为mTOR在T细胞耐受性控制中的关键调节剂的重要性。使用遗传操作的小鼠和细胞系模型，我们最近揭示了RasGRP 1-Ras-Mek 1/2-Erk 1/2通路对于T细胞受体（TCR）刺激后T细胞中的mTORC 1和mTORC 2活化都是至关重要的。我们和其他人还证明了TSC 1抑制mTORC 1，但促进T细胞中的mTORC 2信号传导，并且对正常T细胞稳态很重要。我们对这一提议的中心假设是1）TCR下游的多个信号级联控制mTOR活化和2）TSC 1是通过mTORC 1和mTORC 2信号传导的紧密控制的诱导性Treg和T细胞无反应性的关键调节剂。有了强有力的初步数据，我们计划通过追求三个具体目标来测试我们的假设。在目标1中，我们将研究控制T细胞中mTOR激活的机制。我们将检验Erk 1/2磷酸化多种底物以促进mTORC 1和mTORC 2活化的假设。在目标2中，我们将确定TSC 1如何控制T细胞无能。在目标3中，我们将确定TSC 1如何控制诱导型Treg和辅助性T细胞分化。拟议的研究将为理解mTOR信号传导，TSC 1在T细胞中的重要性以及调节T细胞耐受性的机制提供新的见解。 公共卫生相关性：适当控制T细胞活化和耐受性对于预防自身免疫性疾病的发病机制和建立针对癌症和病原体的有效免疫应答是重要的。该提案中的研究有望提高对调节T细胞活化和耐受性的机制的理解，这将对这些疾病的新治疗策略的开发具有潜在意义。

DESCRIPTION (provided by applicant): T cell tolerance not only is critical in preventing autoimmune diseases but also contributes to tumor tolerance. T cell anergy and regulatory T cells (Treg) are two major forms of peripheral T cell tolerance. However, the specific mechanisms that control T cell anergy and Treg are still not well understood. Rapamycin has been utilized as an immunosuppressant for decades. Its target, the mammalian target of rapamycin (mTOR), is a serine threonine kinase that plays crucial roles in multiple cellular processes by regulating nutrient uptake, transcription, translation, autophagy, and cell survival. mTOR forms two signaling complexes (mTORC1 and mTORC2) with distinct signaling properties and sensitivities to rapamycin. Recent evidence has established mTOR as a crucial regulator for effector T cell differentiation, T cell anergy, inducible regulatory T cell differentiation, and memory T cell responses to viral pathogens. However, the pathways leading to mTOR activation in T cells and the importance of tight control of mTOR activity remain poorly understood. The objective of this proposal is to improve the understanding of mTOR signaling and the importance of the tumor suppressor tuberous complex 1 (TSC1) as a critical regulator for mTOR in the control of T cell tolerance. Using genetically manipulated mice and cell line models, we have recently revealed that the RasGRP1-Ras- Mek1/2-Erk1/2 pathway is critical for both mTORC1 and mTORC2 activation in T cells following T cell receptor (TCR) stimulation. We and others have also demonstrated that TSC1 inhibits mTORC1 but promotes mTORC2 signaling in T cells and is important for normal T cell homeostasis. Our central hypotheses for this proposal are 1) multiple signaling cascades downstream of the TCR control mTOR activation and 2) TSC1 is a critical regulator for inducible Treg and T cell anergy by tight contro of mTORC1 and mTORC2 signaling. With strong preliminary data, we plan to test our hypotheses by pursuing three specific aims. In aim 1, we will investigate the mechanisms that control mTOR activation in T cells. We will test the hypothesis that Erk1/2 phosphorylate multiple substrates to promote mTORC1 and mTORC2 activation. In aim 2, we will determine how TSC1 controls T cell anergy. In aim 3, we will determine how TSC1 controls inducible Treg and helper T cell differentiation. The proposed studies will provide new insight into the understanding of mTOR signaling, the importance of TSC1 in T cells, and the mechanisms modulating T cell tolerance. PUBLIC HEALTH RELEVANCE: Proper control of T cell activation and tolerance is important in preventing the pathogenesis of autoimmune diseases and mounting effective immune responses against cancer and pathogens. Studies in this proposal are expected to improve the understanding of mechanisms that regulate T cell activation and tolerance, which will have potential implications for the development of novel therapeutic strategies for these diseases.