SYK expression endows human ZAP70-deficient CD8 T cells with residual TCR signaling

Fabian Hauck; Britta Blumenthal; Sebastian Fuchs; Christelle Lenoir; Emmanuel Martin; Carsten Speckmann; Thomas Vraetz; Wilma Mannhardt-Laakmann; Nathalie Lambert; Marine Gil; Stephan Borte; Marie Audrain; Klaus Schwarz; Annick Lim; Wolfgang W Schamel; Alain Fischer; Stephan Ehl; Anne Rensing-Ehl; Capucine Picard; Sylvain Latour

doi:10.1016/j.clim.2015.07.002

SYK expression endows human ZAP70-deficient CD8 T cells with residual TCR signaling

Clin Immunol. 2015 Dec;161(2):103-9. doi: 10.1016/j.clim.2015.07.002. Epub 2015 Jul 14.

Authors

Fabian Hauck¹, Britta Blumenthal², Sebastian Fuchs³, Christelle Lenoir⁴, Emmanuel Martin⁴, Carsten Speckmann⁵, Thomas Vraetz⁶, Wilma Mannhardt-Laakmann⁷, Nathalie Lambert⁸, Marine Gil⁸, Stephan Borte⁹, Marie Audrain¹⁰, Klaus Schwarz¹¹, Annick Lim¹², Wolfgang W Schamel², Alain Fischer¹³, Stephan Ehl⁵, Anne Rensing-Ehl¹⁴, Capucine Picard¹⁵, Sylvain Latour¹⁶

Affiliations

¹ 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.
² 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.
³ Center for Chronic Immunodeficiency (CCI), University Medical Center, University of Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
⁴ Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR1163, Institut IMAGINE, Paris, France.
⁵ 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.
⁶ Center for Pediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Germany.
⁷ Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, University Hospital Mainz, Germany.
⁸ Study Center of Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
⁹ ImmunoDeficiencyCenter Leipzig (IDCL), St. Georg Hospital, Leipzig, Germany; Translational Centre for Regenerative Medicine (TRM), University Leipzig, Leipzig, Germany.
¹⁰ Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nantes, France.
¹¹ 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.
¹² Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France.
¹³ 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.
¹⁴ Center for Chronic Immunodeficiency (CCI), University Medical Center, University of Freiburg, Germany.
¹⁵ 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.
¹⁶ 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.

PMID: 26187144
DOI: 10.1016/j.clim.2015.07.002

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.

Keywords: CID; Live vaccine adverse event; SYK; TCR signaling; TREC newborn screening; ZAP70.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / immunology*
Child, Preschool
Humans
Immunologic Deficiency Syndromes / immunology
Infant
Intracellular Signaling Peptides and Proteins / immunology*
Male
Mutation / immunology
Protein-Tyrosine Kinases / immunology*
Receptors, Antigen, T-Cell / immunology*
Retrospective Studies
Severe Combined Immunodeficiency / immunology*
Signal Transduction / immunology
Syk Kinase
ZAP-70 Protein-Tyrosine Kinase / deficiency*
ZAP-70 Protein-Tyrosine Kinase / immunology

Substances

Intracellular Signaling Peptides and Proteins
Receptors, Antigen, T-Cell
Protein-Tyrosine Kinases
SYK protein, human
Syk Kinase
ZAP-70 Protein-Tyrosine Kinase
ZAP70 protein, human

Supplementary concepts

ZAP70 deficiency