title: SYK expression endows human ZAP70-deficient CD8 T cells with residual TCR signaling.
abstract: Autosomal recessive human ZAP70 deficiency is a rare cause of combined immunodeficiency (CID) characterized by defective CD4 T cells and profound CD8 T cell lymphopenia. Herein, we report two novel patients that extend the molecular genetics, the clinical and functional phenotypes associated with the ZAP70 deficiency. The patients presented as infant-onset CID with severe infections caused by varicella zoster virus and live vaccines. Retrospective TCR excision circle newborn screening was normal in both patients. One patient carried a novel non-sense mutation (p.A495fsX75); the other a previously described misense mutation (p.A507V). In contrast to CD4 T cells, the majority of the few CD8 T cells showed expression of the ZAP70-related tyrosine kinase SYK that correlated with residual TCR signaling including calcium flux and degranulation. Our findings highlight the differential requirements of ZAP70 and SYK during thymic development, peripheral homeostasis as well as effector functions of CD4 and CD8 T cells.
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR1163, Institut IMAGINE, Paris, France.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hauck
authors.affiliation: BIOSS Centre for Biological Signalling Studies, Faculty of Biology, University of Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), University Medical Center, University of Freiburg, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Blumenthal
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center, University of Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR1163, Institut IMAGINE, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Lenoir
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR1163, Institut IMAGINE, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Martin
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center, University of Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Center for Pediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vraetz
authors.affiliation: Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, University Hospital Mainz, Germany.
authors.forename: Wilma
authors.initials: W
authors.lastname: Mannhardt-Laakmann
authors.affiliation: Study Center of Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambert
authors.affiliation: Study Center of Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Gil
authors.affiliation: ImmunoDeficiencyCenter Leipzig (IDCL), St. Georg Hospital, Leipzig, Germany; Translational Centre for Regenerative Medicine (TRM), University Leipzig, Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Borte
authors.affiliation: Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nantes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Audrain
authors.affiliation: Institute for Transfusion Medicine, University Hospital Ulm and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Baden-Württemberg-Hessen, Ulm, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.affiliation: BIOSS Centre for Biological Signalling Studies, Faculty of Biology, University of Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), University Medical Center, University of Freiburg, Germany.
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Schamel
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR1163, Institut IMAGINE, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institut, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Collège de France, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center, University of Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center, University of Freiburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, Imagine Institut, Paris, France; Study Center of Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Institut IMAGINE, Necker Medical School, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR1163, Institut IMAGINE, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institut, Paris, France. Electronic address: sylvain.latour@inserm.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002675:Child, Preschool; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008297:Male; D009154:Mutation / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012189:Retrospective Studies; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000172:deficiency* / Q000276:immunology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human
keywords: CID; Live vaccine adverse event; SYK; TCR signaling; TREC newborn screening; ZAP70