Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 3, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201062
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Funding
- Jeffrey Modell Foundation
- Ministry of Health, State of Israel
- Israel Science Foundation Israel PrecisionMedicine Program [3115/19]
- Intramural Research Programof the National Institute of Allergy and Infectious Diseases, National Institutes of Health
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This study identified a novel biallelic mutations in SLP76 gene in an infant with severe immunodeficiency, which resulted in early-onset life-threatening infections and various immunodeficiency effects. By simulating the patient's immune phenotype and intervention research, the study demonstrated the important role of SLP76 in the human immune system.
The T cell receptor (TCR) signaling pathway is an ensemble of numerous proteins that are crucial for an adequate immune response. Disruption of any protein involved in this pathway leads to severe immunodeficiency and unfavorable clinical outcomes. Here, we describe an infant with severe immunodeficiency who was found to have novel biallelic mutations in SLP76. SLP76 is a key protein involved in TCR signaling and in other hematopoietic pathways. Previous studies of this protein were performed using Jurkat-derived human leukemic T cell lines and SLP76-deficient mice. Our current study links this gene, for the first time, to a human immunodeficiency characterized by early-onset life-threatening infections, combined T and B cell immunodeficiency, severe neutrophil defects, and impaired platelet aggregation. Hereby, we characterized aspects of the patient's immune phenotype, modeled them with an SLP76-deficient Jurkat-derived T cell line, and rescued some consequences using ectopic expression of wild-type SLP76. Understanding human diseases due to SLP76 deficiency is helpful in explaining the mixed T cell and neutrophil defects, providing a guide for exploring human SLP76 biology.
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