Université Paris-Sud, Laboratoire "Chemokines and Immunopathology," Unité Mixte de Recherche S996, Clamart, France; INSERM, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Clamart, France;
Institut Cochin, INSERM U1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France; Service de Médecine Interne, Hôpital Cochin, Département Hospitalo-Universitaire Autoimmune and Hormonal Diseases, Assistance Publique-Hôpitaux de Paris, Paris, France;
Blood. 2015 Apr 16;125(16):2507-18. doi: 10.1182/blood-2014-08-598565. Epub 2015 Mar 2.
Idiopathic CD4 lymphopenia (ICL) is a rare heterogeneous immunological syndrome of unclear etiology. ICL predisposes patients to severe opportunistic infections and frequently leads to poor vaccination effectiveness. Chronic immune activation, expansion of memory T cells, and impaired T-cell receptor (TCR) signaling have been reported in ICL, but the mechanistic and causative links remain unclear. We show that late-differentiated T cells in 20 patients with ICL displayed defective TCR responses and aging markers similar to those found in T cells from elderly subjects. Intrinsic T-cell defects were caused by increased expression of dual-specific phosphatase 4 (DUSP4). Normalization of DUSP4 expression using a specific siRNA improved CD4(+) T-cell activity in ICL, as this restored TCR-induced extracellular signal-regulated kinase activation and increased the expression of the costimulatory molecules CD27 and CD40L. Conversely, repeated TCR stimulation led to defective signaling and DUSP4 overexpression in control CD4(+) T cells. This was associated with gradual acquisition of a memory phenotype and was curtailed by DUSP4 silencing. These findings identify a premature T-cell senescence in ICL that might be caused by chronic T-cell activation and a consequential DUSP4-dependent dampening of TCR signaling.
特发性 CD4 淋巴细胞减少症（ICL）是一种罕见的、病因不明的异质性免疫综合征。ICL 使患者易患严重的机会性感染，并经常导致疫苗接种效果不佳。在 ICL 中已经报道了慢性免疫激活、记忆 T 细胞扩增和 T 细胞受体（TCR）信号转导受损，但机制和因果关系仍不清楚。我们发现，20 名 ICL 患者的晚期分化 T 细胞表现出与老年患者 T 细胞相似的 TCR 反应和衰老标志物缺陷。双特异性磷酸酶 4（DUSP4）的过度表达导致了固有 T 细胞缺陷。使用特异性 siRNA 使 DUSP4 表达正常化，改善了 ICL 中 CD4(+) T 细胞的活性，因为这恢复了 TCR 诱导的细胞外信号调节激酶激活，并增加了共刺激分子 CD27 和 CD40L 的表达。相反，反复的 TCR 刺激导致对照 CD4(+) T 细胞中信号转导缺陷和 DUSP4 过表达。这与记忆表型的逐渐获得有关，并通过 DUSP4 沉默得到遏制。这些发现确定了 ICL 中存在过早的 T 细胞衰老，这可能是由慢性 T 细胞激活和随之而来的 DUSP4 依赖性 TCR 信号转导抑制引起的。
