Cheng Chao, Wang Sihua, Ye Ping, Huang Xiaofan, Liu Zheng, Wu Jie, Sun Yuan, Xie Aini, Wang Guohua, Xia Jiahong
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Thoracic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Immunology. 2014 Dec;143(4):618-30. doi: 10.1111/imm.12343.
Regulatory T (Treg) cells play an important role in the maintenance of immune self-tolerance and homeostasis. We previously reported that neonatal CD4(+) T cells have an intrinsic 'default' mechanism to become Treg (neoTreg) cells in response to T-cell receptor (TCR) stimulation. However, the underlying mechanisms are unclear and the effects of neoTreg cells on regulating immune responses remain unknown. Due to their involvement in Foxp3 regulation, we examined the role of DNA methyltransferase 1 (DNMT1) and DNMT3b during the induction of neoTreg cells in the Foxp3(gfp) mice. The function of neoTreg cells was assessed in an acute allograft rejection model established in RAG2(-/-) mice with allograft cardiac transplantation and transferred with syngeneic CD4(+) effector T cells. Following ex vivo TCR stimulation, the DNMT activity was increased threefold in adult CD4(+) T cells, but not significantly increased in neonatal cells. However, adoptively transferred neoTreg cells significantly prolonged cardiac allograft survival (mean survival time 47 days, P < 0.001) and maintained Foxp3 expression similar to natural Treg cells. The neoTreg cells were hypomethylated at the conserved non-coding DNA sequence 2 locus of Foxp3 compared with adult Treg cells. The DNMT antagonist 5-aza-2'-deoxycytidine (5-Aza) induced increased Foxp3 expression in mature CD4(+) T cells. 5-Aza-inducible Treg cells combined with continuous 5-Aza treatment prolonged graft survival. These results indicate that the 'default' pathway of neoTreg cell differentiation is associated with reduced DNMT1 and DNMT3b response to TCR stimulus. The neoTreg cells may be a strategy to alleviate acute allograft rejection.
调节性T（Treg）细胞在维持免疫自身耐受性和体内平衡中发挥着重要作用。我们之前报道过，新生CD4(+) T细胞具有一种内在的“默认”机制，可在T细胞受体（TCR）刺激下转变为Treg（新生Treg）细胞。然而，其潜在机制尚不清楚，新生Treg细胞对调节免疫反应的影响也仍不明确。由于它们参与Foxp3调节，我们在Foxp3(gfp)小鼠中研究了DNA甲基转移酶1（DNMT1）和DNMT3b在新生Treg细胞诱导过程中的作用。在通过同种异体心脏移植建立的急性移植排斥模型中，将同基因CD4(+)效应T细胞转移至RAG2(-/-)小鼠，以此评估新生Treg细胞的功能。体外TCR刺激后，成年CD4(+) T细胞中的DNMT活性增加了三倍，但新生细胞中的DNMT活性没有显著增加。然而，过继转移的新生Treg细胞显著延长了心脏同种异体移植的存活时间（平均存活时间47天，P < 0.001），并维持了与天然Treg细胞相似的Foxp3表达。与成年Treg细胞相比，新生Treg细胞在Foxp3的保守非编码DNA序列2位点处发生低甲基化。DNMT拮抗剂5-氮杂-2'-脱氧胞苷（5-Aza）可诱导成熟CD4(+) T细胞中Foxp3表达增加。5-Aza诱导的Treg细胞与持续的5-Aza处理相结合可延长移植物存活时间。这些结果表明，新生Treg细胞分化的“默认”途径与DNMT1和DNMT3b对TCR刺激的反应降低有关。新生Treg细胞可能是减轻急性移植排斥反应的一种策略。
