Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects

Atar Lev, Yu Nee Lee, Guangping Sun, Enas Hallumi, Amos J. Simon, Keren S. Zrihen, Shiran Levy, Tal Beit Halevi, Maria Papazian, Neta Shwartz, Ido Somekh, Sarina Levy-Mendelovich, Baruch Wolach, Ronit Gavrieli, Helly Vernitsky, Ortal Barel, Elisheva Javasky, Tali Stauber, Chi A. Ma, Yuan ZhangNinette Amariglio, Gideon Rechavi, Ayal Hendel, Deborah Yablonski, Joshua D. Milner, Raz Somech

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21 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere20201062
JournalJournal of Experimental Medicine
Volume218
Issue number3
Early online date24 Nov 2020
DOIs
StatePublished - 1 Mar 2021

Bibliographical note

Publisher Copyright:
© 2020 Lev et al.

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