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iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests.

Authors
  • Themeli, Maria1
  • Chhatta, Amiet2
  • Boersma, Hester3
  • Prins, Henk Jan1
  • Cordes, Martijn2
  • de Wilt, Edwin4
  • Farahani, Aïda Shahrabi1
  • Vandekerckhove, Bart5
  • van der Burg, Mirjam6
  • Hoeben, Rob C3
  • Staal, Frank J T2
  • Mikkers, Harald M M7
  • 1 Department of Hematology, Amsterdam UMC, Location VUmc, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. , (Netherlands)
  • 2 Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. , (Netherlands)
  • 3 Department of Cell & Chemical Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands. , (Netherlands)
  • 4 Department of Clinical Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands. , (Netherlands)
  • 5 Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Gent 9000, Belgium. , (Belgium)
  • 6 Department of Immunology, Erasmus Medical Center, Rotterdam 3015 GE, The Netherlands. , (Netherlands)
  • 7 Department of Cell & Chemical Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; LUMC hiPSC Hotel, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands. Electronic address: [email protected] , (Netherlands)
Type
Published Article
Journal
Stem Cell Reports
Publisher
Elsevier
Publication Date
Feb 11, 2020
Volume
14
Issue
2
Pages
300–311
Identifiers
DOI: 10.1016/j.stemcr.2019.12.010
PMID: 31956083
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

RAG2 severe combined immune deficiency (RAG2-SCID) is a lethal disorder caused by the absence of functional T and B cells due to a differentiation block. Here, we generated induced pluripotent stem cells (iPSCs) from a RAG2-SCID patient to study the nature of the T cell developmental blockade. We observed a strongly reduced capacity to differentiate at every investigated stage of T cell development, from early CD7-CD5- to CD4+CD8+. The impaired differentiation was accompanied by an increase in CD7-CD56+CD33+ natural killer (NK) cell-like cells. T cell receptor D rearrangements were completely absent in RAG2SCID cells, whereas the rare T cell receptor B rearrangements were likely the result of illegitimate rearrangements. Repair of RAG2 restored the capacity to induce T cell receptor rearrangements, normalized T cell development, and corrected the NK cell-like phenotype. In conclusion, we succeeded in generating an iPSC-based RAG2-SCID model, which enabled the identification of previously unrecognized disorder-related T cell developmental roadblocks. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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