Cyclin-dependent kinases: Novel switches in anergy and targets for tolerance

描述（由申请人提供）：自身免疫和器官移植排斥影响超过2500万美国人，每年的经济影响超过1000亿美元。这些炎性疾病是由于限制T细胞活化和分化的内在调节途径的破坏，以及调节性T细胞（Treg）不能体外抑制常规T细胞（Tconv）增殖和效应子功能。在过去的两个资助期内，我们的工作集中在细胞周期蛋白依赖性激酶在T细胞分化，无反应性和耐受性中的作用。我们的工作确定了CDK2及其抑制剂p27kip1在控制免疫和耐受之间的平衡中的关键作用。我们发现，CDK2种系缺失的小鼠在导致野生型受体排斥反应的条件下接受心脏同种异体移植物，而缺乏p27kip1的小鼠对共刺激阻断诱导的耐受性具有高度抗性。令人惊讶的是，这些因子不通过调节T细胞周期进程发挥作用。相反，我们发现CDK2活性促进T辅助细胞分化，并且CDK2缺陷型Treg表现出抑制活性的增加。在这次更新申请中，我们将探索CDK2通路在调节性T细胞功能控制中的这种令人兴奋的新作用，主要集中在我们的发现中，即Foxp3被磷酸化并被CDK2靶向降解，并且失调的CDK2活性对抗Foxp3+ Treg的诱导和稳定性。这项工作将促进我们对Foxp3和调节性T细胞功能如何调节的基本理解，也将具有重要的治疗意义。小分子CDK拮抗剂目前正处于I期临床试验中，根据我们的研究结果，可能用于促进自身免疫和器官移植患者的调节性T细胞功能和耐受性。

DESCRIPTION (provided by applicant): Autoimmunity and organ transplant rejection affect over 25 million Americans, and together have an economic impact of over 100 billion dollars per year. These inflammatory diseases result from a breakdown of the intrinsic regulatory pathways that limit T cell activation and differentiation, and from a failure of regulatory T cells (Treg) t extrinsically suppress conventional T cell (Tconv) proliferation and effector function. Our work during the last two funding periods has focused on the role of cyclin-dependent kinases in T cell differentiation, anergy and tolerance. Our work established critical roles for CDK2 and its inhibitor p27kip1 in controlling the balance between immunity and tolerance. We showed that mice with a germline deletion of CDK2 accept cardiac allografts under conditions that lead to rejection in wild-type recipients, while mice lacking p27kip1 are highly resistant to tolerance induced by costimulatory blockade. Surprisingly, these factors do not operate through regulation of T cell cycle progression. Instead, we found that CDK2 activity promotes T helper differentiation, and that CDK2-deficient Treg exhibit a gain of suppressive activity. In this renewal application, we will explore this exciting new role for the CDK2 pathway in the control of regulatory T cell function, focused mainly by our findings that Foxp3 is phosphorylated and targeted for degradation by CDK2, and that dysregulated CDK2 activity opposes the induction and stability of Foxp3+ Treg. The proposed work will forward our basic understanding of how Foxp3 and regulatory T cell function is regulated, and will also have important therapeutic implications. Small molecule CDK antagonists are currently in phase I clinical trials, and based on our findings, could potentially be used to promote regulatory T cell function and tolerance in autoimmune and organ transplant patients.