Journal
BLOOD
Volume 125, Issue 16, Pages 2507-2518Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-08-598565
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Funding
- Agence Nationale de la Recherche (ANR) [2010-JCJC-110401]
- Programme Hospitalier de Recherche Clinique, French Ministry of Health [2009-01-55]
- ANR [ANR-10-LABX-33, ANR-11-IDEX-0003-01]
- French Ministry
- Fondation pour la Recherche Medicale [FDT20130928127]
- Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique
- Assistance Publique-Hopitaux de Paris
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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 1 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 1 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.
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