Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Immunity. 2018 Aug 21;49(2):247-263.e7. doi: 10.1016/j.immuni.2018.05.006. Epub 2018 Jul 24.
CD4 T cell differentiation into multiple T helper (Th) cell 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 TbetiTreg cells) and inducible regulatory T (iTreg) cells. TbetiTreg 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 TbetiTreg cells and iTreg cells by specifically downregulating endo-lysosomal protease asparaginyl endopeptidase (AEP). AEP regulated Foxp3 stability and blocking AEP imparted regulatory function in TbetiTreg 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 (TILs) and during chronic viral infection. Collectively, this report has identified an intrinsic function for PD-1 in maintaining Foxp3 through proteolytic pathway.
CD4 T 细胞向多种辅助性 T 细胞（Th）谱系的分化对于最佳适应性免疫反应至关重要。本报告确定了程序性死亡受体 1（PD-1）信号赋予 Foxp3 Th1 细胞（表示为 TbetiTreg 细胞）和诱导性调节性 T（iTreg）细胞调节表型的内在机制。TbetiTreg 细胞可预防实验性结肠炎和实验性移植物抗宿主病（GvHD）模型中的炎症。程序性死亡配体 1（PDL-1）与 PD-1 的结合通过特异性地下调内体溶酶体蛋白酶天冬酰胺内肽酶（AEP）赋予 TbetiTreg 细胞和 iTreg 细胞调节功能。AEP 调节 Foxp3 的稳定性，阻断 AEP 可赋予 TbetiTreg 细胞调节功能。此外，Aep iTreg 细胞可显著抑制 GvHD 并维持 Foxp3 的表达。PD-1 在肿瘤浸润淋巴细胞（TIL）和慢性病毒感染过程中均介导 Tbet Th1 细胞中 Foxp3 的维持。总之，本报告确定了 PD-1 通过蛋白水解途径维持 Foxp3 的内在功能。
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