PDF(Pubmed)
Abstract：
T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases, including Juvenile Idiopathic Arthritis (JIA). The molecular mechanisms underlying T cell activation are still incompletely understood. T cell activation promotes the acetylation of histone 3 at Lysine 27 (H3K27ac) at enhancer and promoter regions of proinflammatory cytokines, thereby increasing the expression of these genes which is essential for T cell function. Co-activators E1A binding protein P300 (P300) and CREB binding protein (CBP), collectively known as P300/CBP, are essential to facilitate H3K27 acetylation. Presently, the role of P300/CBP in human CD4+ T cells activation remains incompletely understood. To assess the function of P300/CBP in T cell activation and autoimmune disease, we utilized iCBP112, a selective inhibitor of P300/CBP, in T cells obtained from healthy controls and JIA patients. Treatment with iCBP112 suppressed T cell activation and cytokine signaling pathways, leading to reduced expression of many proinflammatory cytokines, including IL-2, IFN-γ, IL-4, and IL-17A. Moreover, P300/CBP inhibition in T cells derived from the inflamed synovium of JIA patients resulted in decreased expression of similar pathways and preferentially suppressed the expression of disease-associated genes. This study underscores the regulatory role of P300/CBP in regulating gene expression during T cell activation while offering potential insights into the pathogenesis of autoimmune diseases. Our findings indicate that P300/CBP inhibition could potentially be leveraged for the treatment of autoimmune diseases such as JIA in the future.
摘要：
T细胞活化对于针对病原体的有效免疫应答是关键的。然而,失调有助于自身免疫性疾病的发病机制，包括幼年特发性关节炎（JIA）。T细胞活化的分子机制仍未完全了解。T细胞活化促进组蛋白3在赖氨酸27（H3K27ac）的乙酰化，在促炎细胞因子的增强子和启动子区域，从而增加这些对T细胞功能至关重要的基因的表达。共激活剂E1A结合蛋白P300（P300）和CREB结合蛋白（CBP），统称为P300/CBP，是促进H3K27乙酰化所必需的。目前,P300/CBP在人CD4+T细胞活化中的作用尚不完全清楚.评估P300/CBP在T细胞活化和自身免疫性疾病中的功能，我们使用了iCBP112，P300/CBP的选择性抑制剂，在从健康对照和JIA患者获得的T细胞中。iCBP112治疗抑制T细胞活化和细胞因子信号通路，导致许多促炎细胞因子的表达减少，包括IL-2，IFN-γ，IL-4和IL-17A。此外，来自JIA患者发炎滑膜的T细胞中的P300/CBP抑制导致相似途径的表达降低，并优先抑制疾病相关基因的表达。这项研究强调了P300/CBP在T细胞活化过程中调节基因表达的调节作用，同时为自身免疫性疾病的发病机理提供了潜在的见解。我们的发现表明，P300/CBP抑制可能在未来用于治疗自身免疫性疾病，如JIA。
