Biomedical Research Center, Ulsan University Hospital, School of Medicine, University of Ulsan, Korea.
Biol Blood Marrow Transplant. 2012 Jan;18(1):44-54. doi: 10.1016/j.bbmt.2011.09.004. Epub 2011 Sep 28.
CD25(+)CD4(+)Foxp3(+) regulatory T cells (Tregs) play a pivotal role in the maintenance of self-tolerance and regulation of immune responses. Previous studies have demonstrated that CD137 signals can promote proliferation and survival of Tregs in vitro. Here, we show that in vivo CD137-induced expansion of Tregs in naive mice was dependent upon IL-2 secreted by memory T cells. Tregs primed by anti-CD137 mAbs had a higher immunosuppressive capacity. Preconditioning with anti-CD137 mAbs significantly inhibited graft-versus-host disease (GVHD) in the C57BL/6 → (C57BL/6 × DBA/2) F1 acute GVHD model. In this disease model, a high proportion of host Tregs remained long-term in the recipient spleen, whereas donor hematopoietic cells replaced other host bone marrow-derived cells. Transient depletion of Tregs before transfer of donor cells completely abrogated the inhibitory effect of anti-CD137 mAbs on GVHD. In addition, adoptive transfer of anti-CD137-primed Tregs ameliorated GVHD. Our results demonstrate that it is possible to enhance the survival and/or the immunosuppressive activity of host Tregs in nonmyeloablative GVHD, and that 1 way of accomplishing this is through the prophylactic use of anti-CD137 mAbs in nonmyeloablative GVHD.
CD25(+)CD4(+)Foxp3(+) 调节性 T 细胞 (Tregs) 在维持自身耐受和调节免疫反应中发挥着关键作用。先前的研究表明，CD137 信号可以促进体外 Tregs 的增殖和存活。在这里，我们表明在幼稚小鼠中，CD137 诱导的 Tregs 扩增依赖于记忆 T 细胞分泌的 IL-2。通过抗 CD137 mAbs 诱导的 Tregs 具有更高的免疫抑制能力。用抗 CD137 mAbs 预处理可显著抑制 C57BL/6→(C57BL/6×DBA/2)F1 急性移植物抗宿主病 (GVHD) 模型中的 GVHD。在这种疾病模型中，大量宿主 Tregs 在受体脾脏中长期存在，而供体造血细胞取代了其他宿主骨髓来源的细胞。在输注供体细胞之前短暂耗尽 Tregs，完全消除了抗 CD137 mAbs 对 GVHD 的抑制作用。此外，过继转移抗 CD137 诱导的 Tregs 可改善 GVHD。我们的结果表明，有可能增强非清髓性 GVHD 中宿主 Tregs 的存活和/或免疫抑制活性，一种实现这一目标的方法是在非清髓性 GVHD 中预防性使用抗 CD137 mAbs。
