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

J Exp Med. 2021 Mar 1;218(3):e20201062. doi: 10.1084/jem.20201062.

Atar Lev ¹ ², Yu Nee Lee ¹, Guangping Sun ³, Enas Hallumi ⁴, Amos J Simon ¹ ⁵, Keren S Zrihen ¹, Shiran Levy ¹, Tal Beit Halevi ¹, Maria Papazian ¹, Neta Shwartz ¹, Ido Somekh ⁶, Sarina Levy-Mendelovich ⁷, Baruch Wolach ⁸, Ronit Gavrieli ⁸, Helly Vernitsky ⁵, Ortal Barel ⁹ ¹⁰, Elisheva Javasky ⁹ ¹⁰, Tali Stauber ¹, Chi A Ma ³, Yuan Zhang ³ ¹¹, Ninette Amariglio ² ¹², Gideon Rechavi ¹⁰ ¹³, Ayal Hendel ², Deborah Yablonski ⁴, Joshua D Milner ³ ¹¹, Raz Somech ¹ ¹³

Affiliations

1 Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
2 The Mina and Everard Goodman Faculty of Life Sciences, Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat Gan, Israel.
3 Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
4 Department of Immunology, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
5 Division of Haematology and Bone Marrow Transplantation, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
6 Department of Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
7 The Israeli National Hemophilia Center and Thrombosis Unit, The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
8 Department of Pediatrics and Laboratory for Leukocyte Function, Meir Medical Center, Kfar Saba, Israel.
9 The Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel.
10 Cancer Research Center, Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel.
11 Department of Pediatrics, Columbia University Irving Medical Center, New York, NY.
12 Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
13 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

PMID: 33231617 DOI: 10.1084/jem.20201062

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.

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