Functional protein networks underlying T cell growth, proliferation and differentiation

项目总结： 正常的免疫功能对人类健康至关重要。CD4T细胞是适应性免疫的中心成分 免疫来协调先天免疫和获得性免疫反应。免疫抑制调节T细胞(Treg) 细胞在免疫动态平衡和自我耐受中起着关键作用，它们的功能是通过 不同的机制，允许Treg细胞对不同的环境线索做出适当的反应，以确保 适当的免疫反应。研究T和Treg的功能蛋白质网络是很重要的 细胞在免疫动态平衡和疾病中的作用。我们已经确定了许多关键因素、途径和 T细胞和Treg细胞在上一个资助阶段的功能机制，在此期间，我们发现了一个意想不到的 在最近的一项研究中，先天性感受器AIM2(在黑色素瘤2中缺失)在控制Treg细胞功能中起着关键作用。 我们发现AIM2在Treg细胞中的表达水平远远高于在先天细胞中的表达水平，在这两个人中 还有老鼠。转化生长因子β促进AIM2的表达与Treg细胞的生成相一致。与ASC-/-和ICE-/-不同 (caspase-1-/-11-/-)对EAE有抵抗力的小鼠，AIM2-/-小鼠比WT小鼠发展成更严重的EAE。 AIM2缺失会导致EAE等炎症性疾病中Treg细胞功能降低。AIM2是必填项 对于Treg细胞的稳定性，以缓解EAE。AIM2缺乏导致Akt-mTOR信号通路过度激活 通过改变免疫代谢来减弱Treg细胞的功能。这些令人兴奋的发现促使我们提出假设 AIM2在Treg细胞中的表达和功能是通过不同于 并与先天细胞中发现的那些共享，以维持耐受性和抑制自身免疫。为了测试这一点 在假设的基础上，我们力求达到以下研究目的。目的1：揭示基因和分子 转化生长因子β促进Treg细胞表达AIM2的机制目的2：研究AIM2是否控制Treg细胞 通过整合DNA传感功能和炎症体成分发挥作用。目标3：机构学研究 AIM2控制的Treg细胞功能的功能与AIM2相互作用的蛋白质网络。 这项拟议的研究将强调AIM2在Treg细胞中以前未被认识到的关键作用。会的 通过结合AIM2的Treg细胞特异性功能来修订当前的AIM2功能范例。会的 为Treg细胞的生成和功能如何调控提供新的见解。它将为我们带来新的曙光 Treg细胞功能的分子网络和揭示潜在的新分子靶点和治疗方法 治疗自身免疫性疾病。

Project Summary: Proper immune function is pivotal to the human health. CD4+ T cell is a central component of adaptive immunity to coordinate both innate and adaptive immune responses. Immune suppressive regulatory T (Treg) cells are pivotal in immune homeostasis and self-tolerance, and their function is controlled through quite diverse mechanisms, allowing Treg cells to respond appropriately to diverse environmental cues to ensure proper immune response. It is important to investigate the functional protein networks underlying T and Treg cell function in immune homeostasis and diseases. We have identified many critical factors, pathways, and mechanisms for T and Treg cell function in the last funding period, during which we revealed an unexpected critical role for an innate senor AIM2 (Absent In Melanoma 2) in controlling Treg cell function in a recent study. We found that AIM2 is expressed at much higher levels in Treg cells than in innate cells, in both human and mouse. TGFβ promotes AIM2 expression coinciding with Treg cell generation. Unlike Asc-/- and ICE-/- (caspase-1-/-11-/--) mice that are resistant to EAE, Aim2-/- mice developed more severe EAE than WT mice. AIM2 deletion leads to reduced Treg cell function during inflammatory diseases such as EAE. AIM2 is required for Treg cell stability to mitigate EAE. AIM2-deficiency leads to the hyper-activation of Akt-mTOR signaling to attenuate Treg cell function with altered immune metabolism. These exciting findings prompt us to hypothesize that the expression and function of AIM2 in Treg cells are controlled through mechanisms both distinct from and shared with those found in the innate cells, to uphold tolerance and restrain autoimmunity. To test this hypothesis, we strive to reach the following research aims. AIM 1: Reveal the genetic and molecular mechanisms of TGFβ promoted Aim2 expression in Treg cells. AIM 2: Investigate if AIM2 controls Treg cell function by integrating DNA-sensing function and inflammasome components. AIM 3: Mechanistic study of the functional AIM2-interacting protein network underlying AIM2 controlled Treg cell function. This proposed study will highlight a previously unappreciated critical role for AIM2 in Treg cells. It will revise the current paradigm for the function of AIM2 by incorporating its Treg cell specific function. It will provide new insights into how Treg cell generation and function can be regulated. It will shed new lights on the molecular networks underlying Treg cell function and to reveal potential novel molecular targets and therapies for autoimmune diseases.