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The generation of T cells from pluripotent stem cells (PSCs) is attractive for investigating T cell development and validating genome editing strategies  in vitro . X-linked severe combined immunodeficiency (X-SCID) is an immune disorder caused by mutations in the  IL2RG  gene and characterised by the absence of T and NK cells in patients.  IL2RG  encodes the common gamma chain, which is part of several interleukin receptors, including IL-2 and IL-7 receptors. To model X-SCID  in vitro , we generated a mouse embryonic stem cell (ESC) line in which a disease-causing human  IL2RG  gene variant replaces the endogenous  Il2rg  locus. We developed a stage-specific T cell differentiation protocol to validate genetic correction of the common G691A mutation with transcription activator-like effector nucleases. While all ESC clones could be differentiated to hematopoietic precursor cells, stage-specific analysis of T cell maturation confirmed early arrest of T cell differentiation at the T cell progenitor stage in X-SCID cells. In contrast, genetically corrected ESCs differentiated to CD4 + or CD8 + single-positive T cells, confirming correction of the cellular X-SCID phenotype. This study emphasises the value of PSCs for disease modelling and underlines the significance of  in vitro  models as tools to validate genome editing strategies before clinical application.

Targeted genome editing restores T cell differentiation in a humanized X-SCID pluripotent stem cell disease model