DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia.
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.
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;
Alexandre
A
Bignon
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;
Alexis
A
Régent
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;
Laurence
L
Klipfel
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;
Aude
A
Desnoyer
GenoSplice, Hôpital Pitié-Salpêtrière, Paris, France;
Pierre
P
de la Grange
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; Service de Médecine Interne et d'Immunologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Antoine-Béclère, Clamart, France;
Valérie
V
Martinez
Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Centre d'Infectiologie Necker-Pasteur, Institut Hospitalo-Universitaire Imagine, Hôpital Necker-Enfants Malades, Paris, France; and Institut Pasteur, Unité de Mycologie Moléculaire, Centre National de la Recherche Scientifique Unité de Recherche Associée 3012, Paris, France.
Olivier
O
Lortholary
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;
Ali
A
Dalloul
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;
Luc
L
Mouthon
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;
Karl
K
Balabanian
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology*; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome / Q000276:immunology; D055815:Young Adult
D011948:Receptors, Antigen, T-Cell; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases