Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen-specific tolerance.
Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen-specific tolerance.
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DOI：
10.1002/eji.200635883
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发表时间：
2006-06
影响因子：
5.4
通讯作者：
Wang, Ping
中科院分区：
文献类型：
--
作者：
Anderson, Per O;Manzo, Barbara A;Sundstedt, Anette;Minaee, Sophie;Symonds, Alistair;Khalid, Sabah;Rodriguez-Cabezas, Maria E;Nicolson, Kirsty;Li, Suling;Wraith, David C;Wang, Ping
体内重复抗原刺激诱导外周T细胞耐受。然而，目前尚不清楚多重刺激是否仅仅抑制T细胞激活，或者将转录程序改变为一种独特的耐受状态。在本研究中，我们发现体内STAT3和STAT5在抗原刺激下被激活，与AP-1、NF-κB和NFAT的抑制形成明显对比。此外，在体内抗原激发后，耐受性T细胞中诱导了许多转录因子，包括T-bet， Irf-1和Egr-2。耐受性细胞中转录程序的改变与细胞周期进程和IL-2产生的抑制以及IL-10的诱导密切相关。对T-bet和Egr-2的研究表明，在肽处理诱导的调节性T细胞中，T-bet的功能与Th1分化无关，但与IL-2的抑制有关，而Egr-2的表达导致细胞周期抑制剂p21cip1和p27kip的上调。我们的研究结果表明，在抗原诱导的T细胞反应中，一个由不同转录因子调节的平衡转录程序对T细胞活化和/或耐受起作用。持续抗原刺激可通过改变转录因子的平衡诱导T细胞耐受。
Repetitive antigen stimulation induces peripheral T cell tolerance in vivo. It is not known, however, whether multiple stimulations merely suppress T cell activation or, alternatively, change the transcriptional program to a distinct, tolerant state. In this study, we have discovered that STAT3 and STAT5 were activated in response to antigen stimulation in vivo, in marked contrast to the suppression of AP-1, NF-κB and NFAT. In addition, a number of transcription factors were induced in tolerant T cells following antigen challenge in vivo, including T-bet, Irf-1 and Egr-2. The altered transcription program in tolerant cells associates closely with the suppression of cell cycle progression and IL-2 production, as well as with the induction of IL-10. Studies of T-bet and Egr-2 show that the function of T-bet in peptide treatment-induced regulatory T cells is not associated with Th1 differentiation, but correlates with the suppression of IL-2, whereas expression of Egr-2 led to an up-regulation of the cell cycle inhibitors p21cip1 and p27kip. Our results demonstrate a balanced transcription program regulated by different transcription factors for T cell activation and/or tolerance during antigen-induced T cell responses. Persistent antigen stimulation can induce T cell tolerance by changing the balance of transcription factors.