The PDL1-PD1 axis converts human TH1 cells into regulatory T cells.
The PDL1-PD1 axis converts human TH1 cells into regulatory T cells.
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DOI：
10.1126/scitranslmed.3003130
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发表时间：
2011-11-30
影响因子：
17.1
通讯作者：
Fowler DH
中科院分区：
文献类型：
--
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
1型辅助性T细胞（Th 1）的免疫监视对于宿主对肿瘤和感染的反应至关重要，但也有助于移植后的自身免疫和移植物抗宿主病（GvHD）。抑制性分子程序性死亡配体-1（PDL 1）已显示使人Th 1细胞无反应，但PDL 1介导的Th 1抑制的其他机制，如Th 1细胞向调节表型的转化尚未得到很好的表征。我们推测PDL 1可能导致Th 1细胞表现出分化可塑性。常规T细胞或过表达PDL 1的经辐照的K562骨髓肿瘤细胞在体内将TBET+ Th 1细胞转化为FOXP 3+调节性T细胞（TREGS），从而防止人到小鼠的异种GvHD（xGvHD）。通过siRNA靶向阻断Th 1细胞上的PD 1表达或通过SHP 1/2药理学抑制消除PD 1信号传导在PDL 1攻击期间稳定Th 1细胞分化并恢复Th 1细胞介导致死性xGVHD的能力。因此，PD 1信号传导诱导人Th 1细胞表现出体内可塑性，导致严重损害细胞介导的免疫的TREG表型。将人Th 1细胞转化为具有PD 1信号传导的调节表型提供了在移植后阻断GvHD的潜在方法。此外，由于这种转化可以通过阻断PD 1表达或抑制SHP 1/2来阻止，因此该途径为增强T细胞对癌症和感染的免疫力提供了新的治疗方向。
Immune surveillance by T helper type 1 (Th1) cells is critical for the host response to tumors and infection, but also contributes to autoimmunity and graft-versus-host disease (GvHD) after transplantation. The inhibitory molecule programmed death ligand-1 (PDL1) has been shown to anergize human Th1 cells, but other mechanisms of PDL1-mediated Th1 inhibition such as the conversion of Th1 cells to a regulatory phenotype have not been well characterized. We hypothesized that PDL1 may cause Th1 cells to manifest differentiation plasticity. Conventional T cells or irradiated K562 myeloid tumor cells overexpressing PDL1 converted TBET+ Th1 cells into FOXP3+ regulatory T cells (TREGS) in vivo, thereby preventing human-into-mouse xenogeneic GvHD (xGvHD). Either blocking PD1 expression on Th1 cells by siRNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized Th1 cell differentiation during PDL1 challenge and restored the capacity of Th1 cells to mediate lethal xGVHD. PD1 signaling therefore induces human Th1 cells to manifest in vivo plasticity, resulting in a TREG phenotype that severely impairs cell-mediated immunity. Converting human Th1 cells to a regulatory phenotype with PD1 signaling provides a potential way to block GvHD after transplantation. Moreover, because this conversion can be prevented by blocking PD1 expression or pharmacologically inhibiting SHP1/2, this pathway provides a new therapeutic direction for enhancing T cell immunity to cancer and infection.
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影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
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：
30.5
作者：
Latchman, Y;Wood, CR;Freeman, GJ
通讯作者：
Freeman, GJ
影响因子：
4.4
作者：
Blazar, BR;Carreno, BM;Taylor, PA
通讯作者：
Taylor, PA
影响因子：
4.4
作者：
Holland, Steven M.
通讯作者：
Holland, Steven M.