PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells.
PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells.
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DOI：
10.1016/j.immuni.2018.05.006
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发表时间：
2018-08-21
期刊：
影响因子：
32.4
通讯作者：
Amarnath S
中科院分区：
文献类型：
--
作者：
Stathopoulou C;Gangaplara A;Mallett G;Flomerfelt FA;Liniany LP;Knight D;Samsel LA;Berlinguer-Palmini R;Yim JJ;Felizardo TC;Eckhaus MA;Edgington-Mitchell L;Martinez-Fabregas J;Zhu J;Fowler DH;van Kasteren SI;Laurence A;Bogyo M;Watts C;Shevach EM;Amarnath S
CD4+ T细胞分化为多个辅助性T细胞（Th）谱系是最佳适应性免疫反应的关键。本报告确定了程序性死亡-1受体（PD-1）信号传导将调节性表型传递给Foxp3+ Th1细胞（Tbet+iTregPDL1细胞）和诱导调节性T细胞（iTregs）的内在机制。Tbet+iTregPDL1细胞可预防实验性结肠炎和实验性移植物抗宿主病（GvHD）小鼠模型的炎症。与PD-1结合的程序性死亡配体-1 （PDL-1）通过特异性下调内切溶酶体蛋白酶天门酰胺内肽酶（AEP），对Tbet+iTregPDL1细胞和iTreg细胞具有调节功能。AEP可调节Foxp3的稳定性，阻断AEP可在Tbet+iTreg细胞中发挥调节功能。此外，Aep−/−iTreg细胞显著抑制GvHD并维持Foxp3的表达。PD-1介导的Tbet+ Th1细胞Foxp3维持发生在肿瘤浸润淋巴细胞（TIL）和慢性病毒感染期间。总的来说，本报告已经确定了PD-1通过蛋白水解途径维持Foxp3的内在功能。Th1细胞以其增强的稳定性而闻名，因此，介导其灵活性的机制研究甚少。在这里，Stathopoulou等人证明了Th1细胞对Tbet+iTreg细胞的可塑性是由PD-1信号通过天冬酰胺内肽酶（AEP）介导的。AEP抑制可增强GvHD和肿瘤模型中的iTreg细胞。
CD4+ T cell differentiation into multiple T helper cell (Th) lineages is critical for optimal adaptive immune responses. This report identifies an intrinsic mechanism by which programmed death-1 receptor (PD-1) signaling imparted regulatory phenotype to Foxp3+ Th1 cells (denoted as Tbet+iTregPDL1 cells) and inducible regulatory T cells (iTregs). Tbet+iTregPDL1 cells prevented inflammation in murine models of experimental colitis and experimental graft versus host disease (GvHD). Programmed death ligand-1 (PDL-1) binding to PD-1 imparted regulatory function to Tbet+iTregPDL1 cells and iTreg cells by specifically down regulating endo-lysosomal protease asparaginyl endopeptidase (AEP). AEP regulated Foxp3 stability and blocking AEP imparted regulatory function in Tbet+iTreg cells. Also, Aep−/− iTreg cells significantly inhibited GvHD and maintained Foxp3 expression. PD-1 mediated Foxp3 maintenance in Tbet+ Th1 cells occurred both in tumor infiltrating lymphocytes (TIL) and during chronic viral infection. Collectively, this report has identified an intrinsic function for PD-1 in maintaining Foxp3 through proteolytic pathway. Th1 cells are known for their enhanced stability, therefore, mechanisms which mediate their flexibility are poorly studied. Here, Stathopoulou et al, demonstrate that plasticity of Th1 cells to Tbet+iTreg cells is mediated by PD-1 signaling via asparaginyl endopeptidase (AEP). AEP inhibition enhances iTreg cells in GvHD and tumor models.
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控制FOXP3基因座中的顺式元素对调节T细胞身份的遗传控制。
影响因子：
64.5
作者：
Feng Y;Arvey A;Chinen T;van der Veeken J;Gasteiger G;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
17.1
作者：
Amarnath S;Mangus CW;Wang JC;Wei F;He A;Kapoor V;Foley JE;Massey PR;Felizardo TC;Riley JL;Levine BL;June CH;Medin JA;Fowler DH
通讯作者：
Fowler DH
影响因子：
32.4
作者：
Hegazy, Ahmed N.;Peine, Michael;Loehning, Max
通讯作者：
Loehning, Max
影响因子：
32.4
作者：
Bailey-Bucktrout, Samantha L.;Martinez-Llordella, Marc;Zhou, Xuyu;Anthony, Bryan;Rosenthal, Wendy;Luche, Herve;Fehling, Hans J.;Bluestone, Jeffrey A.
通讯作者：
Bluestone, Jeffrey A.