Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen-specific tolerance

被引:53
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 [1 ]
机构
[1] Barts & London Sch Med & Dent, Inst Cell & Mol Sci, London EC1A 7ED, England
[2] Univ Bristol, Sch Med Sci, Dept Pathol & Microbiol, Bristol BS8 1TH, Avon, England
[3] Brunel Univ, Dept Biol Sci, Microarray Grp, London, England
基金
英国惠康基金;
关键词
cell activation; signal transduction; T cells; tolerance; transcription factors;
D O I
10.1002/eji.200635883
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-kappa B 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 p21(cip1) and p27(kip). 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.
引用
收藏
页码:1374 / 1385
页数:12
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