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

细胞周期蛋白依赖性激酶：无反应性的新开关和耐受性目标

基本信息

批准号：
9173017
负责人：
ANDREW D WELLS
金额：
$ 42万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9173017
关键词：
Address Adoptive Transfer Affect American Antigens Atypical lymphocyte Autoimmune Process Autoimmunity Biochemical Pathway Biological Assay Biological Markers CD4 Positive T Lymphocytes CDK2 gene Cell Cycle Progression Cell division Cell physiology Cells Chronic Coupled Cyclin-Dependent Kinases Data Disease Effector Cell Equilibrium Exhibits FOXP3 gene Failure Funding Gene Expression Profiling Genetic Models Genetic Transcription Growth Factor Receptors Homeostasis Immune Cell Activation Immune system Immunity In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-6 Lead Link Measurement Modeling Monitor Mus Nuclear Organ Transplantation Pathway interactions Pharmaceutical Preparations Phase I Clinical Trials Phosphorylation Physiological Population Process Property Proteins Regulatory Pathway Regulatory T-Lymphocyte Resistance Role Signal Transduction Stimulus T cell differentiation T cell regulation T-Cell Activation T-Lymphocyte Therapeutic Transforming Growth Factor beta Transplant Recipients Ubiquitination Work adaptive immunity anergy base cell growth cytokine economic impact heart allograft immunoregulation in vivo Model inhibitor/antagonist mutant novel oral tolerance organ transplant rejection programs public health relevance response small molecule

项目摘要

DESCRIPTION (provided by applicant): The proliferation of a few, antigen-reactive lymphocytes into a large population of effector cells is a fundamental property of adaptive immunity. The cell division that fuels this process is driven by signals from antigen, costimulatory and growth factor receptors, and is controlled by the cyclin-dependent kinase (CDK) cascade. 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.

描述（由申请人提供）：少数抗原反应性淋巴细胞扩散到大量的效应细胞中是适应性免疫的基本特性。燃料该过程的细胞分裂是由来自抗原，共刺激和生长因子受体的信号驱动的，并且受细胞周期蛋白依赖性激酶（CDK）级联反应的控制。在过去两个资金期间，我们的工作集中于细胞周期蛋白依赖性激酶在T细胞分化，不良和耐受性中的作用。我们的工作确立了CDK2及其抑制剂P27KIP1在控制免疫和耐受性之间的关键作用。我们表明，在导致野生型受体排斥的条件下，具有CDK2种系缺失的小鼠接受心脏同种异体移植物，而缺乏P27KIP1的小鼠对通过cont虫阻塞引起的耐受性具有很高的抵抗力。令人惊讶的是，这些因素不能通过调节T细胞周期进程来运作。取而代之的是，我们发现CDK2活性促进了T辅助分化，并且缺乏CDK2的TREG表现出抑制活性的增长。在此续签应用中，我们将探索CDK2途径在控制调节性T细胞功能中的这种令人兴奋的新作用，这主要是由于我们的发现是Foxp3被磷酸化并靶向CDK2降解，并且CDK2活性失调会反对Foxp3+ Treg的诱导和稳定性。拟议的工作将使我们对FOXP3和调节性T细胞功能的调节方式的基本理解，也将具有重要的治疗意义。小分子CDK拮抗剂目前正在I期临床试验中，根据我们的发现，可以使用自身免疫和器官移植患者的调节性T细胞功能和耐受性。