Chongqing Key Laboratory of Child Infection and Immunity, Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorder, International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, 17177, Sweden.
Sci Rep. 2017 Sep 20;7(1):11978. doi: 10.1038/s41598-017-12345-z.
Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton. Defective T - cell function is a major cause for immune deficiency in Wiskott-Aldrich syndrome (WAS) patients. T cells originate in the bone marrow and develop in the thymus, and then migrate to peripheral tissues. TCR excision circles (TRECs) present in thymic output cells stably, which is used as a molecular marker for thymic output. We found that CD8 T naïve cells of classic WAS patients were significantly reduced, and TRECs in patients with classic WAS and X-linked thrombocytopenia (XLT) dramatically decreased compared with that of HCs. TRECs were also reduced in WAS (KO) mice. These suggest that defective thymic output partially accounts for T cell lymphopenia in WAS patients. However, the correlation between the defect of thymic output and actin organization still remains elusive. We found that the subcellular location and the levels of of F-actin were altered in T cells from both WAS and XLT patients compared to that of HCs with or without stimulation. Our study shows that WASp plays a critical role in thymic output, which highly correlates with the subcellular location and level of F-actin in T cells.
Wiskott-Aldrich 综合征蛋白（WASp）是细胞骨架肌动蛋白的关键调节因子。T 细胞功能缺陷是 Wiskott-Aldrich 综合征（WAS）患者免疫缺陷的主要原因。T 细胞起源于骨髓，在胸腺中发育，然后迁移到外周组织。TCR 切除环（TRECs）稳定存在于胸腺输出细胞中，可作为胸腺输出的分子标志物。我们发现经典 WAS 患者的 CD8 T 幼稚细胞明显减少，与健康对照者相比，经典 WAS 和 X 连锁血小板减少症（XLT）患者的 TRECs 显著减少。WAS（KO）小鼠的 TRECs 也减少。这表明胸腺输出缺陷部分导致了 WAS 患者的 T 细胞淋巴细胞减少。然而，胸腺输出缺陷与肌动蛋白组织之间的相关性仍不清楚。我们发现与健康对照者相比，无论是刺激后还是无刺激，来自 WAS 和 XLT 患者的 T 细胞的细胞内定位和 F-肌动蛋白的水平都发生了改变。我们的研究表明，WASp 在胸腺输出中发挥着关键作用，这与 T 细胞中 F-肌动蛋白的细胞内定位和水平高度相关。
