Laboratory of Clinical Immunology, Faculty of Medicine, KU Leuven, Leuven, Belgium.
Eur J Immunol. 2013 Apr;43(4):1013-23. doi: 10.1002/eji.201242737. Epub 2013 Feb 22.
Costimulatory signals are required for priming and activation of naive T cells, while it is less clear how they contribute to induction of regulatory T (Treg)-cell activity. We previously reported that the blockade of the B7-CD28 and CD40L-CD40 interaction efficiently suppresses allogeneic T-cell activation in vivo. This was characterized by an initial rise in Foxp3(+) cells, followed by depletion of host-reactive T cells. To further investigate effects of costimulatory blockade on Treg cells, we used an in vitro model of allogeneic CD4(+) cell activation. When CTLA-4Ig and anti-CD40L mAb (MR1) were added to the cultures, T-cell proliferation and IL-2 production were strongly reduced. However, Foxp3(+) cells proliferated and acquired suppressive activity. They suppressed activation of syngeneic CD4(+) cells much more efficiently than did freshly isolated Treg cells. CD4(+) cells activated by allogeneic cells in the presence of MR1 and CTLA-4Ig were hyporesponsive on restimulation, but their response was restored to that of naive CD4(+) cells when Foxp3(+) Treg cells were removed. We conclude that natural Treg cells are less dependent on B7-CD28 or CD40-CD40L costimulation compared with Foxp3(-) T cells. Reduced costimulation therefore alters the balance between Teff and Treg-cell activation in favor of Treg-cell activity.
共刺激信号对于初始 T 细胞的激活和激活是必需的，而它们如何有助于诱导调节性 T（Treg）细胞的活性则不太清楚。我们之前报道过，阻断 B7-CD28 和 CD40L-CD40 相互作用可有效抑制体内同种异体 T 细胞的激活。其特征是 Foxp3(+)细胞的初始增加，随后宿主反应性 T 细胞耗竭。为了进一步研究共刺激阻断对 Treg 细胞的影响，我们使用了同种异体 CD4(+)细胞激活的体外模型。当 CTLA-4Ig 和抗 CD40L mAb (MR1) 添加到培养物中时，T 细胞增殖和 IL-2 产生被强烈抑制。然而，Foxp3(+)细胞增殖并获得了抑制活性。它们比新鲜分离的 Treg 细胞更有效地抑制同源 CD4(+)细胞的激活。在 MR1 和 CTLA-4Ig 的存在下由同种异体细胞激活的 CD4(+)细胞在再刺激时反应性降低，但当去除 Foxp3(+)Treg 细胞时，其反应恢复为幼稚 CD4(+)细胞的反应。我们得出结论，与 Foxp3(-)T 细胞相比，天然 Treg 细胞对 B7-CD28 或 CD40-CD40L 共刺激的依赖性较低。因此，减少共刺激会改变效应 T 细胞和 Treg 细胞激活之间的平衡，有利于 Treg 细胞的激活。
