Protein kinase A-dependent regulation of T cell accumulation in Lupus

描述(由申请人提供)：确定PKA-I活性不足如何导致T细胞效应器功能异常是了解SLE患者T细胞功能障碍的病因的关键一步。在正常人T细胞中，强的PKA激活剂PGE2抑制IL-2诱导的IL-13+细胞的体外积聚，而弱的PKA激活剂β-激动剂导致IL-13+细胞的积聚增加。在PKA活性严重缺陷的SLE患者中，PGE2和ISO均导致IL-2诱导的IL-13+细胞积聚显著增加。R21的应用旨在阐明PKA缺陷对SLE受试者T细胞聚集的调节特征的影响。假说是，在β-激动剂和PGE2的刺激下，PKA活性缺陷的SLE受试者亚群中有夸大的2型细胞积累。进一步的假设是，PKA RI？亚基的实验敲除/表达足以引起/逆转这一效应。这些假说将使用高度解释性的体外模型和一组特征良好的系统性红斑狼疮受试者进行验证。这些研究结果将为T细胞生物学基础科学感兴趣的T细胞发育调控提供新的见解，并促进我们对SLE免疫系统调控的理解。

DESCRIPTION (provided by applicant): Establishing how deficient PKA-I activity results in abnormal T cell effector functions is a key step in understanding the etiopathogenesis of T cell dysfunction in SLE. In T cells from normal subjects, IL-2 induced IL-13+ cell accumulation in vitro is inhibited by the strong PKA activator PGE2, whereas the weak PKA activator beta-agonist causes increased accumulation. In SLE subjects with a severe defect in PKA activity, both PGE2 and ISO cause a profound increase in IL-2 induced IL-13+ cell accumulation. This R21 application proposes to clarify the effect of defective PKA on regulatory features of T cell accumulation in SLE subjects. The hypothesis is that the subpopulation of SLE subjects with defects in PKA activity has exaggerated accumulation of type 2 cells when stimulated by beta-agonist and PGE2. Further hypothesis is that experimental knockdown/expression of the PKA RI¿-subunit is sufficient to cause/reverse this effect. These hypotheses will be tested using a highly interpretive in vitro model and a well characterized cohort of SLE subjects. Results from these studies will provide novel insight into the regulation of T cell development of interest to the basic science of T cell biology, and advance our understanding of immune system regulation in SLE.