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: 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
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 161 Issue 2 Pg. 103-9 (Dec 2015) ISSN: 1521-7035 [Electronic] United States
• PMID: 26187144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• 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, immunology)