Open AccessInherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects
Author(s) -
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 LevyMendelovich,
Baruch Wolach,
Ronit Gavrieli,
Helly Vernitsky,
Ortal Barel,
Elisheva Javasky,
Tali Stauber,
Aiping Chi,
Yuan Zhang,
Ninette Amariglio,
Gideon Rechavi,
Ayal Hendel,
Deborah Yablonski,
Joshua D. Milner,
Raz Somech
Publication year - 2020
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20201062
Subject(s) - jurkat cells , immunodeficiency , immunology , t cell receptor , severe combined immunodeficiency , biology , immune system , t cell , primary immunodeficiency , immune dysregulation , phenotype , signal transduction , gene , microbiology and biotechnology , genetics
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.