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.
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 SCIDCD34(+) 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.
Authors: Kimberly G Laffey; Robert J Stiles; Melissa J Ludescher; Tessa R Davis; Shariq S Khwaja; Richard J Bram; Peter J Wettstein; Venkataraman Ramachandran; Christopher A Parks; Edwin E Reyes; Alejandro Ferrer; Jenna M Canfield; Cory E Johnson; Richard D Hammer; Diana Gil; Adam G Schrum Journal: Proc Natl Acad Sci U S A Date: 2022-06-29 Impact factor: 12.779
Authors: Marita Bosticardo; Francesca Pala; Enrica Calzoni; Ottavia M Delmonte; Kerry Dobbs; Cameron L Gardner; Nicolo' Sacchetti; Tomoki Kawai; Elizabeth K Garabedian; Debbie Draper; Jenna R E Bergerson; Suk See DeRavin; Alexandra F Freeman; Tayfun Güngör; Nicholas Hartog; Steven M Holland; Donald B Kohn; Harry L Malech; Mary Louise Markert; Katja G Weinacht; Anna Villa; Christopher S Seet; Amelie Montel-Hagen; Gay M Crooks; Luigi D Notarangelo Journal: Blood Adv Date: 2020-06-23
Authors: Laura Garcia-Perez; Marja van Eggermond; Lieke van Roon; Sandra A Vloemans; Martijn Cordes; Axel Schambach; Michael Rothe; Dagmar Berghuis; Chantal Lagresle-Peyrou; Marina Cavazzana; Fang Zhang; Adrian J Thrasher; Daniela Salvatori; Pauline Meij; Anna Villa; Jacques J M Van Dongen; Jaap-Jan Zwaginga; Mirjam van der Burg; H Bobby Gaspar; Arjan Lankester; Frank J T Staal; Karin Pike-Overzet Journal: Mol Ther Methods Clin Dev Date: 2020-03-31 Impact factor: 6.698
Authors: Carolyn H Baloh; Samiksha A Borkar; Kai-Fen Chang; Jiqiang Yao; Michael S Hershfield; Suhag H Parikh; Donald B Kohn; Maureen M Goodenow; John W Sleasman; Li Yin Journal: J Clin Immunol Date: 2021-06-28 Impact factor: 8.317