Development and function of regulatory T cells

B7/CD28共刺激需要在胸腺中产生功能成熟的CD4+CD25+Foxp3+调节性T细胞。然而，目前尚不清楚B7/CD28共刺激是否也需要维持外周的调节功能。我们开发了一种实验系统，在该系统中，胸腺内B7/CD28共刺激可诱导Foxp3+ Treg细胞的产生，但在Treg细胞所在的外周没有B7/CD28共刺激。我们发现外周淋巴器官持续的共刺激需要通过维持Treg细胞高水平的CTLA-4表达来维持Treg细胞的低反应性和调节功能。我们还发现，CTLA-4在Tregs中紧密定位于细胞质膜下，这种独特的分布有利于其有效抑制TCR信号，并有助于诱导Tregs的低反应性和调节功能。我们的研究结果表明，通过持续共刺激在Treg细胞中维持CTLA-4的高水平表达对Treg细胞功能至关重要。

B7/CD28 costimulation is required to generate functional mature CD4+CD25+Foxp3+ regulatory T cells in the thymus. However, its not known whether B7/CD28 costimulation is also required to maintain regulatory function in the periphery. We developed an experimental system in which B7/CD28 costimulation was available in the thymus to induce the generation of Foxp3+ Treg cells, but B7/CD28 costimulation was absent from the periphery where Treg cells resided. We discovered that persistent costimulation in peripheral lymphoid organ is required to maintain Treg cell hyporesponsiveness and regulatory function through maintaining high level CTLA-4 expression in Tregs. We also found that CTLA-4 in Tregs is closely localized under the cytoplasmic membrane and this unique distribution facilitates its efficient inhibition of TCR signaling and contributes to the induction of hyporesponsiveness and regulatory function in Tregs. Our results indicate that maintaining high level expression of CTLA-4 in Tregs by persistent costimulation is critical for Treg cell function.