Early kinetic window of target T cell susceptibility to CD25+ regulatory T cell activity
Early kinetic window of target T cell susceptibility to CD25+ regulatory T cell activity
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DOI：
10.4049/jimmunol.175.11.7274
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Fowell, DJ
中科院分区：
文献类型：
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作者：
Sojka, DK;Hughson, A;Fowell, DJ
外周耐受性部分由胸腺衍生的CD25（+）CD4（+）T细胞（调节性T细胞（T细胞））维持。其作用机制尚未得到很好的表征。因此，为了更好地理解Treg作用，我们研究了体外鼠Treg活性的动力学。在一个令人惊讶的狭窄动力学窗口内，THBE是抑制性的：仅在培养的前6 - 10小时内是必要和足够的。使用灵敏的IL-2单细胞测定法对该时间范围进行可视化，显示尽管存在CD25（+）CD4（+）T细胞，但在前6小时内靶细胞IL-2产生者的早期加工。然而，在6小时后，在没有Tcl4的情况下IL-2产生者的数量的快速上升被Tcl4的存在显著地消除。重要的是，抑制的时间由靶T细胞活化的动力学决定，这表明早期靶T细胞信号可能改变对抑制的易感性。通过提供CD 28、IL-2或高剂量的抗原来调节靶T细胞激活信号都消除了培养后期对增殖的抑制。然而，只有CD28信号使靶T细胞能够抵抗早期Treg诱导的IL-2下调。因此，早期靶T细胞活化信号的质量，特别是CD28的参与，代表了对Treg抑制的脆弱性和抗性之间平衡的重要控制点。
Peripheral tolerance is maintained in part by thymically derived CD25(+)CD4(+) T cells (regulatory T cells (Tregs)). Their mechanism of action has not been well characterized. Therefore, to get a better understanding of Treg action, we investigated the kinetics of murine Treg activity in vitro. Tregs were suppressive within a surprisingly narrow kinetic Window: necessary and sufficient only in the first 6-10 h of culture. Visualization of this time frame, using a sensitive single-cell assay for IL-2, revealed the early elaboration of target cell IL-2 producers in the first 6 h despite the presence of CD25(+)CD4(+) Tregs. However, after 6 h, a rapid rise in the number of IL-2 producers in the absence of Tregs was dramatically abrogated by the presence of Tregs. Importantly, the timing of suppression was dictated by the kinetics of target T cell activation suggesting that early target T cell signals may alter susceptibility to suppression. Modulating target T cell activation signals with provision of CD28, IL-2, or high Ag dose all abrogated suppression of proliferation late in culture. However, only CD28 signals enabled target T cells to resist the early Treg-induced down-regulation of IL-2. Therefore the quality of early target T cell activation signals, in particular engagement of CD28, represents an important control point in the balance between vulnerability and resistance to Treg suppression.