DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cellular Senescence / genetics
  • Cellular Senescence / immunology*
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / immunology*
  • Dual-Specificity Phosphatases / metabolism
  • Female
  • Flow Cytometry
  • Humans
  • Immunophenotyping
  • Lymphocyte Activation / immunology
  • Lymphopenia / genetics
  • Lymphopenia / immunology*
  • Lymphopenia / metabolism
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Mitogen-Activated Protein Kinase Phosphatases / immunology*
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism
  • Oligonucleotide Array Sequence Analysis
  • RNA Interference / immunology
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transcriptome / immunology
  • Young Adult


  • Receptors, Antigen, T-Cell
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP4 protein, human
  • Dual-Specificity Phosphatases

Associated data

  • GEO/GSE56998