FOXP3型
调节性T细胞
免疫系统
免疫学
PI3K/AKT/mTOR通路
生发中心
周边公差
生物
自身免疫
CD8型
T细胞
免疫失调
平衡
细胞生物学
B细胞
信号转导
白细胞介素2受体
抗体
作者
Akhilesh K. Singh,Fahd Al Qureshah,Travis Drow,Baidong Hou,David J. Rawlings
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2024-06-03
卷期号:213 (2): 135-147
标识
DOI:10.4049/jimmunol.2400032
摘要
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.
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