Peptide dose, affinity, and time of differentiation can contribute to the Th1/Th2 cytokine balance.
Peptide dose, affinity, and time of differentiation can contribute to the Th1/Th2 cytokine balance.
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DOI：
10.4049/jimmunol.163.3.1205
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发表时间：
1999-08
影响因子：
4.4
通讯作者：
Paul R. Rogers;Michael Croft
中科院分区：
文献类型：
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作者：
Paul R. Rogers;Michael Croft
关于 Ag 剂量和亲和力如何调节 Th1/Th2 分化存在相反的观点，数据表明高水平和低水平刺激都有利于 Th2 反应。对于带有单一 TCR 的转基因 T 细胞，我们使用对 TCR 亲和力不同的肽提供了新的数据，表明随着初始刺激水平的改变，分化的时间段可以决定 Th1 或 Th2 反应是否占主导地位。在短期内，与产生IL-4的细胞相比，产生IFN-γ的细胞受到较低水平的刺激的诱导，尽管在相同的高水平刺激下观察到两者的最佳诱导。然而，从长远来看，高剂量的高亲和力肽选择性地导致IFN-γ分泌细胞，而IL-4和IL-5分泌细胞占主导地位，初始信号传导水平较低，这是由中等剂量的高亲和力肽引起的。相反，在幼稚 T 细胞阶段，任何浓度的低亲和力肽的刺激水平太低，只能促进 IL-2 分泌效应子，或者不足以维持 T 细胞的长期存活。这些结果表明，通过 TCR 实现的信号传导水平与不同细胞因子分泌 T 细胞的诱导密切相关。我们发现，剂量、亲和力、分化发生的时间以及 IL-4 和 IFN-γ 的初始产生都可以影响 T 细胞亚群占主导地位。此外，这些数据调和了关于剂量和亲和力影响的两种相反观点，并提供了基于信号强度和反应长度的 Th1/Th2 分化的统一模型。
Opposing viewpoints exist regarding how Ag dose and affinity modulate Th1/Th2 differentiation, with data suggesting that both high and low level stimulation favors Th2 responses. With transgenic T cells bearing a single TCR, we present novel data, using peptides differing in affinity for the TCR, that show that the time period of differentiation can determine whether Th1 or Th2 responses predominate as the level of initial stimulation is altered. Over the short term, IFN-gamma-producing cells were induced by lower levels of stimulation than IL-4-producing cells, although optimal induction of both was seen with the same high level of stimulation. Over the long term, however, high doses of high affinity peptides led selectively to IFN-gamma-secreting cells, whereas IL-4- and IL-5-secreting cells predominated with lower levels of initial signaling, brought about by moderate doses of high affinity peptides. In contrast, too low a level of stimulation at the naive T cell stage, with low affinity peptides at any concentration, promoted only IL-2-secreting effectors or was not sufficient for long term T cell survival. These results demonstrate that the level of signaling achieved through the TCR is intimately associated with the induction of distinct cytokine-secreting T cells. We show that dose, affinity, time over which differentiation occurs, and initial production of IL-4 and IFN-gamma all can contribute to which T cell subset will predominate. Furthermore, these data reconcile the two opposing views on the effects of dose and affinity and provide a unifying model of Th1/Th2 differentiation based on strength of signaling and length of response.