PDF(Pubmed)
Abstract：
FOXP3+ regulatory T cells (Treg) are required for maintaining immune tolerance and preventing systemic autoimmunity. PI3Kδ is required for normal Treg development and function. However, the impacts of dysregulated PI3Kδ signaling on Treg function remain incompletely understood. In this study, we used a conditional mouse model of activated PI3Kδ syndrome to investigate the role of altered PI3Kδ signaling specifically within the Treg compartment. Activated mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) specifically within the Treg compartment exhibited weight loss and evidence for chronic inflammation, as demonstrated by increased memory/effector CD4+ and CD8+ T cells with enhanced IFN-γ secretion, spontaneous germinal center responses, and production of broad-spectrum autoantibodies. Intriguingly, aPIK3CD facilitated Treg precursor development within the thymus and an increase in peripheral Treg numbers. Peripheral Treg, however, exhibited an altered phenotype, including increased PD-1 expression and reduced competitive fitness. Consistent with these findings, Treg-specific aPIK3CD mice mounted an elevated humoral response following immunization with a T cell-dependent Ag, which correlated with a decrease in follicular Treg. Taken together, these findings demonstrate that an optimal threshold of PI3Kδ activity is critical for Treg homeostasis and function, suggesting that PI3Kδ signaling in Treg might be therapeutically targeted to either augment or inhibit immune responses.
摘要：
FOXP3+调节性T细胞(Treg)是维持免疫耐受和预防全身性自身免疫所必需的。PI3Kδ是正常Treg发育和功能所必需的。然而,PI3Kδ信号传导失调对Treg功能的影响仍未完全理解。在这项研究中,我们使用激活的PI3Kδ综合征的条件性小鼠模型来研究在Treg区室中特异性改变的PI3Kδ信号传导的作用。在Treg区室中特别表达PIK3CD功能获得突变（aPIK3CD）的激活小鼠表现出体重减轻和慢性炎症的证据。如增加的记忆/效应CD4+和CD8+T细胞与增强的IFN-γ分泌，自发的生发中心反应，和广谱自身抗体的生产。有趣的是，aPIK3CD促进了胸腺内的Treg前体发展和外周Treg数量的增加。外周Treg,然而,表现出改变的表型，包括PD-1表达增加和竞争力下降。与这些发现一致，Treg特异性aPIK3CD小鼠在用T细胞依赖性Ag免疫后，体液反应升高，这与卵泡Treg的减少有关。一起来看,这些发现表明，PI3Kδ活性的最佳阈值对于Treg稳态和功能至关重要，提示Treg中的PI3Kδ信号传导可能是治疗靶向的,以增强或抑制免疫应答。
