ArticleBlood2016
Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies.
Article in Blood, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 47 citations in OpenAlex.
- RAG1 lentiviral gene therapy restores T-cell development of RAG1-SCID patient cells in artificial thymic organoids.Blood advances · 2025Trial
- Single-cell transcriptomics reveals diversity and conservation of chicken lymphocytes.Poultry science · 2026Article
- HEB collaborates with TCR signaling to upregulatebioRxiv : the preprint server for biology · 2025Article
- Adoptive Cell Therapy from the Dish: Potentiating Induced Pluripotent Stem Cells.Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie · 2025Review
- CRISPR-Cas9 engineering of the RAG2 locus via complete coding sequence replacement for therapeutic applications.Nature communications · 2023Article
- 'Off the shelf' immunotherapies: Generation and application of pluripotent stem cell-derived immune cells.Cell proliferation · 2023Review
- Multiplex HDR for disease and correction modeling of SCID by CRISPR genome editing in human HSPCs.Molecular therapy. Nucleic acids · 2023Article
- Direct regulation of TCR rearrangement and expression by E proteins during early T cell development.WIREs mechanisms of disease · 2022Review
- Review
- Generation and Hematopoietic Differentiation of Mesenchymal Stromal/Stem Cell-Derived Induced Pluripotent Stem Cell Lines for Disease Modeling of Hematopoietic and Immunological Diseases.Methods in molecular biology (Clifton, N.J.) · 2022Article
- NovelFrontiers in pediatrics · 2022Article
- Review
- Review
- Gene Editing Rescues In vitro T Cell Development of RAG2-Deficient Induced Pluripotent Stem Cells in an Artificial Thymic Organoid System.Journal of clinical immunology · 2021Article
- Cutting Edge: TCR-β Selection Is Required at the CD4Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches.European journal of immunology · 2021Review
- The Metabolic Landscape of Thymic T Cell DevelopmentFrontiers in immunology · 2021Article
- Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects.Frontiers in immunology · 2021Review
- Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells.Frontiers in immunology · 2021Review
- Induced Pluripotent Stem Cell Meets Severe Combined Immunodeficiency.Cell journal · 2020Review
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Authors and funding
23 authors at 11 institutions in 5 countries.
Funding
Abstract
Primary immunodeficiency diseases comprise a group of heterogeneous genetic defects that affect immune system development and/or function. Here we use in vitro differentiation of human induced pluripotent stem cells (iPSCs) generated from patients with different recombination-activating gene 1 (RAG1) mutations to assess T-cell development and T-cell receptor (TCR) V(D)J recombination. RAG1-mutants from severe combined immunodeficient (SCID) patient cells showed a failure to sustain progression beyond the CD3(--)CD4(-)CD8(-)CD7(+)CD5(+)CD38(-)CD31(-/lo)CD45RA(+) stage of T-cell development to reach the CD3(-/+)CD4(+)CD8(+)CD7(+)CD5(+)CD38(+)CD31(+)CD45RA(-) stage. Despite residual mutant RAG1 recombination activity from an Omenn syndrome (OS) patient, similar impaired T-cell differentiation was observed, due to increased single-strand DNA breaks that likely occur due to heterodimers consisting of both an N-terminal truncated and a catalytically dead RAG1. Furthermore, deep-sequencing analysis of TCR-β (TRB) and TCR-α (TRA) rearrangements of CD3(-)CD4(+)CD8(-) immature single-positive and CD3(+)CD4(+)CD8(+) double-positive cells showed severe restriction of repertoire diversity with preferential usage of few Variable, Diversity, and Joining genes, and skewed length distribution of the TRB and TRA complementary determining region 3 sequences from SCID and OS iPSC-derived cells, whereas control iPSCs yielded T-cell progenitors with a broadly diversified repertoire. Finally, no TRA/δ excision circles (TRECs), a marker of TRA/δ locus rearrangements, were detected in SCID and OS-derived T-lineage cells, consistent with a pre-TCR block in T-cell development. This study compares human T-cell development of SCID vs OS patients, and elucidates important differences that help to explain the wide range of immunologic phenotypes that result from different mutations within the same gene of various patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.