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

描述（由申请人提供）：确定PKA-I活性缺陷如何导致T细胞效应子功能异常是理解SLE中T细胞功能障碍的发病机制的关键步骤。在来自正常受试者的T细胞中，IL-2诱导的IL-13+细胞体外积累被强PKA激活剂PGE 2抑制，而弱PKA激活剂β-激动剂导致积累增加。在PKA活性严重缺陷的SLE受试者中，PGE 2和ISO都会导致IL-2诱导的IL-13+细胞积聚大幅增加。该R21申请旨在阐明PKA缺陷对SLE受试者中T细胞蓄积的调节特征的影响。假设是PKA活性缺陷的SLE受试者亚群在β-激动剂和PGE 2刺激时具有过度的2型细胞积累。进一步的假设是，PKA RI亚基的实验性敲低/表达足以引起/逆转这种效应。将使用高度解释性的体外模型和充分表征的SLE受试者队列来检验这些假设。这些研究的结果将为T细胞生物学基础科学的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.