PRMT5 Associates With the FOXP3 Homomer and When Disabled Enhances Targeted p185erbB2/neu Tumor Immunotherapy
PRMT5 Associates With the FOXP3 Homomer and When Disabled Enhances Targeted p185erbB2/neu Tumor Immunotherapy
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DOI：
10.3389/fimmu.2019.00174
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发表时间：
2019-02-08
影响因子：
7.3
通讯作者：
Greene, Mark I.
中科院分区：
文献类型：
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作者：
Nagai, Yasuhiro;Ji, Mei Q.;Greene, Mark I.
调节性T细胞（Regulatory T cells，Tcells）是一种专门抑制免疫反应的T细胞亚群。在这里，我们表明，精氨酸甲基转移酶蛋白PRMT 5可以与FOXP 3转录因子在THEX中复合。在TcB中PRMT 5表达的条件性敲除（cKO）的小鼠产生严重的皮屑样自身免疫。在这些PRMT 5 cKO小鼠中，脾脏具有减少数量的TlR，但在外周淋巴结中发现正常数量的TlR。然而，这些缺乏PRMT 5的外周T细胞显示出有限的抑制功能。质谱分析表明，FOXP 3可以在R27、R51和R146位二甲基化。精氨酸（R）51至赖氨酸（K）的点突变导致人CD 4 T细胞中抑制功能缺陷。DS-437对PRMT 5的药理学抑制作用也降低了人Treg功能并抑制了FOXP 3的甲基化。此外，DS-437通过抑制Treg功能和诱导肿瘤免疫，显著增强了抗erbB 2/neu单克隆抗体靶向治疗在携带CT 26 Her 2肿瘤的Balb/c小鼠中的抗肿瘤作用。控制PRMT 5活性是在宿主对肿瘤的免疫以FOXP 3依赖性方式减弱的情况下用于癌症治疗的有前景的策略。
Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner.