PI3Ks增功能突变对胸腺T细胞发育的影响尚不清楚。我们确诊20余例PIK3CD增功能突变（即PI3Kδ过度活化综合征，APDS）患者，其T细胞受体删除环水平明显降低。构建的Pik3cd基因E1024K定点增功能突变小鼠模型中，其胸腺DN3阶段细胞向DN4发育受阻，提示PIK3CD增功能突变对胸腺T细胞发育有重要影响。APDS患者外周T细胞无氧糖酵解增强，导致初始T细胞稳态及T细胞亚群失衡；既往研究显示胸腺细胞发育受糖代谢影响。由此，我们提出科学假设：PIK3CD增功能突变可通过活化Akt-mTOR信号，影响胸腺细胞糖代谢、细胞增殖或细胞凋亡而致胸腺T细胞发育受损。本研究将以Pik3cd突变小鼠为研究对象，探讨PIK3CD增功能突变影响胸腺T细胞发育的具体环节及机制。科学假设的验证不仅可为胸腺T细胞发育过程中的调控机制提供新线索，亦可为APDS患者精准治疗提供更可靠的科学依据。

PI3K-Akt-mTOR pathway palys crucial roles in cell growth, survival, proliferation, and apoptosis. Studies confirmed that PI3Ks loss of function mutation affect thymocyte development, but the role of the PI3Ks gain of function (GOF) mutation in thymocyte development remain unknown. We identified considerable amount of patients with activated phosphoinositide 3-kinase δ syndrome (APDS) in China and found that exflux of naive T cells and TRECs levels were extremely low in APDS patients. We also established a Pik3cd gene E1024K knock-in mice, and found that the difference of double negative T cells in thymus between knock-in mice and wild-type (WT) mice.These findings suggested that GOF mutation of PIK3CD may also affect thymocyte development. Peripheral T cell of APDS patients were prone to activation-induced cell death, and enhanced glucose uptake, and thus interfere with peripheral T cell subsets balance. Moreover, GOF mutations in PIK3CD disrupt naive T cell homeostatis and promote the activation of naive T cells by promoting the aerobic glycolysis program. Previous studies have shown that PI3K-Akt-mTOR pathway is closely related to glucose metabolism, and thymocyte development is affected by glucose metabolism. Here in the present study, we established a Pik3cd gene knock-in mice. In the knock-in mice and WT mice, the thymus will be harvested and used for analysis of different stages of thymocytes and test the glucose metabolism, cell proliferation, and cell apoptosis using flow cytometry, qRT-PCR, and Western blotting. Taken together, we hypothesize that GOF mutation of PIK3CD activating PI3K-Akt-mTOR pathway, may disturbed the development of thymocyte by regulating glucose metabolism, cell proliferation, and cell apoptosis. The present study is innovative. The research findings will be proved helpful not only in understanding the new mechanisms regulating thymocyte development, but also in favor of the precise treatment of APDS patients.