State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, People's Republic of China.
Blood. 2012 Aug 23;120(8):1624-32. doi: 10.1182/blood-2011-11-390708. Epub 2012 Jul 13.
Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure attacked by autoreactive effector T cells and BM is the main target organ. CD4(+)CD25(+) regulatory T cells (Tregs) were believed to control development and progression of autoimmunity by suppressing autoreactive effector T cells, but little was known regarding the function of Tregs in AA. Our study demonstrated that both peripheral blood (PB) and BM had decreased frequencies of Tregs, accompanied with a reversed lower ratio of Treg frequencies between BM and PB in AA. PB Tregs in AA had impaired migratory ability because of lower CXCR4 (but not for CXCR7) expression. Interestingly, we first showed that impairment of Treg-mediated immunosuppression was intrinsic to Tregs, rather than resistance of effector T cells to suppression in AA by coculture assays and criss-cross experiments in vitro. Furthermore, Tregs in AA were less able to inhibit interferon-γ production by effector T cells. Defective immunosuppression by Tregs could contribute to impaired hematopoiesis conducted by effector T cells in vitro. Our study provided powerful evidence that impairment of Tregs played a critical role in the pathophysiology of AA. Thus, patients with AA might greatly benefit from a Treg-oriented immunosuppressive strategy.
获得性再生障碍性贫血 (AA) 是一种由自身反应性效应 T 细胞攻击骨髓 (BM) 引起的骨髓衰竭疾病，BM 是主要的靶器官。CD4(+)CD25(+)调节性 T 细胞 (Tregs) 通过抑制自身反应性效应 T 细胞来控制自身免疫的发展和进展，但对于 Tregs 在 AA 中的作用知之甚少。我们的研究表明，AA 患者的外周血 (PB) 和 BM 中 Tregs 的频率均降低，同时伴有 AA 中 BM 和 PB 之间 Treg 频率的比例颠倒降低。AA 患者的 PB Tregs 由于 CXCR4（而非 CXCR7）表达降低而迁移能力受损。有趣的是，我们首次通过体外共培养和交叉实验表明，AA 中 Treg 介导的免疫抑制受损是 Treg 本身的内在缺陷，而不是效应 T 细胞对抑制的抵抗。此外，AA 中的 Tregs 抑制效应 T 细胞产生干扰素-γ的能力降低。Tregs 的免疫抑制功能缺陷可能导致效应 T 细胞在体外造血功能受损。我们的研究提供了有力的证据，表明 Tregs 的功能障碍在 AA 的病理生理学中起着关键作用。因此，AA 患者可能会从以 Treg 为导向的免疫抑制策略中获益匪浅。
