Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells.
J Allergy Clin Immunol
; 137(2): 517-526.e3, 2016 Feb.
Article
em En
| MEDLINE
| ID: mdl-26441229
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco
/
Linfócitos T
/
Diferenciação Celular
/
Imunodeficiência Combinada Severa
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Holanda