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

描述（由申请人提供）：T细胞无反应性是外周耐受的一种重要机制，其控制自身免疫和移植实验模型中免疫病理学的发展，并且在人类临床器官移植期间最有可能起作用。无反应性涉及不适当的T细胞应答的功能失活，并且被认为是效应基因如白细胞介素-2（IL-2）的主动沉默的结果。我们在该资助的第一个资助期内取得的进展确定了细胞周期进展对于活化的T细胞在生产性免疫反应期间逃避无反应性是必要的，并确定了细胞周期蛋白依赖性激酶（CDK）及其遗传编码的抑制蛋白在T细胞免疫和耐受性之间的决定中的先前未被重视的作用。这些激酶的活性在体外对抗T细胞克隆无能的诱导，并且在器官移植期间CDK活性的遗传失调干扰由共刺激阻断诱导的耐受。 本提案的目的是探索细胞周期蛋白依赖性激酶调节T淋巴细胞功能的分子机制，并评估这些分子作为器官移植临床前模型治疗靶点的潜力。对T细胞耐受性背后的分子事件的更深入了解可能会导致在自身免疫和移植背景下诱导耐受性的新方法，因此本申请中提出的研究与NIH/HHS改善人类健康的目标一致且高度相关。

DESCRIPTION (provided by applicant): T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and transplantation, and is most likely operative during clinical organ transplantation in humans. Anergy involves the functional inactivation of inappropriate T cell responses, and is thought to be the result of active silencing of effector genes such as interleukin-2 (IL-2). Our progress during the first funding period of this grant established that cell cycle progression is necessary for activated T cells to escape anergy during a productive immune response, and defined a previously unappreciated role for cyclin-dependent kinases (CDK) and their genetically-encoded inhibitory proteins in the decision between T cell immunity and tolerance. The activity of these kinases opposed the induction of T cell clonal anergy in vitro, and genetic dysregulation of CDK activity during organ transplantation interfered with tolerance induced by costimulatory blockade. PUBLIC HEALTH RELEVANCE The goal of this proposal is to explore the molecular mechanisms by which cyclin-dependent kinases regulate T lymphocyte function, and to evaluate the potential of these molecules as therapeutic targets in pre-clinical models of organ transplantation. A deeper understanding of the molecular events underlying T cell tolerance could lead to new approaches to induce tolerance in the setting of autoimmunity and transplantation, and therefore the research proposed in the is application is consistent with and highly relevant to the NIH/HHS goal of improving human health.