Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells - 05/02/16
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Abstract |
Background |
Severe combined immunodeficiency (SCID) represents congenital disorders characterized by a deficiency of T cells caused by arrested development in the thymus. Yet the nature of these developmental blocks has remained elusive because of the difficulty of taking thymic biopsy specimens from affected children.
Objective |
We sought to identify the stages of arrest in human T-cell development caused by various major types of SCID.
Methods |
We performed transplantation of SCID CD34+ bone marrow stem/progenitor cells into an optimized NSG xenograft mouse model, followed by detailed phenotypic and molecular characterization using flow cytometry, immunoglobulin and T-cell receptor spectratyping, and deep sequencing of immunoglobulin heavy chain (IGH) and T-cell receptor δ (TRD) loci.
Results |
Arrests in T-cell development caused by mutations in IL-7 receptor α (IL7RA) and IL-2 receptor γ (IL2RG) were observed at the most immature thymocytes much earlier than expected based on gene expression profiling of human thymocyte subsets and studies with corresponding mouse mutants. T-cell receptor rearrangements were functionally required at the CD4−CD8−CD7+CD5+ stage given the developmental block and extent of rearrangements in mice transplanted with Artemis-SCID cells. The xenograft model used is not informative for adenosine deaminase–SCID, whereas hypomorphic mutations lead to less severe arrests in development.
Conclusion |
Transplanting CD34+ stem cells from patients with SCID into a xenograft mouse model provides previously unattainable insight into human T-cell development and functionally identifies the arrest in thymic development caused by several SCID mutations.
Le texte complet de cet article est disponible en PDF.Key words : SCID, thymus, NSG, IL2RG, IL7RA, adenosine deaminase, Artemis, T-cell development, B-cell development
Abbreviations used : ADA, BM, DN, HSPC, IGH, IL2RG, IL7RA, IMDM, LUMC, NK, NSG, SCID, TCR, TRD, UCB
Plan
Supported by KiKa (Children Cancer Free, grant no. 36), ZonMW E-RARE (grant no. 40-41900-98-020), NWO (Vidi grant no. 91712323) and the Netherlands Institute for Regenerative Medicine (NIRM). |
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Disclosure of potential conflict of interest: A.-S. Wiekmeijer has received her salary and travel support from a grant provided by KIKA. J. J. M. van Dongen has consultant arrangements with Roche; has received payment for lectures from BD Biosciences and Pfizer; has patents with and receives royalties from DAKO, InVivoScribe, BD Biosciences, Cytognos, and Immunostep; and has received travel support from Roche and BD Biosciences. W. E. Fibbe has received an H2020 grant. M. van der Burg has received a grant from ZonMW Vidi (9.171.2323). F. J. T. Staal has received research support from KIKA and the European Union; has received travel support from ZonMw SCID gene therapy grants and the European Union; and is employed by Leiden University Medical Center. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 137 - N° 2
P. 517 - février 2016 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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