PI3Kγ和PI3Kδ对T细胞同种免疫的调节。,Nature Communications

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PI3Kγ和PI3Kδ对T细胞同种免疫的调节。
Nature Communications ( IF 14.7 ) Pub Date : 2017-10-16 , DOI: 10.1038/s41467-017-00982-x
Mayuko Uehara , Martina M. McGrath , Shunsuke Ohori , Zhabiz Solhjou , Naima Banouni , Sujit Routray , Catherine Evans , Jonathan P. DiNitto , Abdallah Elkhal , Laurence A. Turka , Terry B. Strom , Stefan G. Tullius , David G. Winkler , Jamil Azzi , Reza Abdi

磷脂酰肌醇-3-激酶（PI3K）的γ和δ优先富集在白细胞中，这些信号通路中的缺陷已显示出损害T细胞活化的作用。PI3Kγ和PI3Kδ对同种免疫的影响尚待探索。在这里，我们显示接受心脏同种异体移植的PI3Kγ ^-/-和PI3KδD910A ^{/ D910A}小鼠均具有抑制同种反应性T效应细胞和延迟急性排斥反应的能力。但是，PI3Kδ突变也会抑制调节性T细胞（Treg）。用低剂量CTLA4-Ig，PI3Kγ ^-/-而不是^{PI3KδD910A / D910A治疗后}，接受者的心脏移植存活期无限延长。PI3Kδ ^{D910A / D910A}Tregs增加了细胞凋亡并损害了生存。对PI3Kγ和PI3Kδ的选择性抑制（使用PI3Kδ和双重PI3Kγδ化学抑制剂）表明，PI3Kγ抑制作用弥补了PI3Kδ抑制作用对同种异体移植长期存活的负面影响。这些数据为将来基于PI3K的移植免疫疗法奠定了基础。磷脂酰肌醇3激酶（PI3K）的γ和δ是T细胞信号转导的关键调节因子。在这里，作者显示，使用小鼠心脏同种异体移植模型，PI3Kγ或PI3Kδ缺乏会延长移植物的存活，但是对PI3Kγ或PI3Kδ的选择性抑制显示出CTLA4-Ig治疗后的替代移植存活结果。

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Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ.

Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ ^-/- and PI3Kδ ^D910A/D910A mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kδ mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kγ ^-/- , but not PI3Κδ ^D910A/D910A , recipients exhibit indefinite prolongation of heart allograft survival. PI3Kδ ^D910A/D910A Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation.Phosphatidylinositol-3-kinases (PI3K) γ and δ are key regulators of T cell signaling. Here the author show, using mouse heart allograft transplantation models, that PI3Kγ or PI3Kδ deficiency prolongs graft survival, but selective inhibition of PI3Kγ or PI3Kδ reveals alternative transplant survival outcomes post CTLA4-Ig treatment.

更新日期：2017-10-16

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