iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests

Maria Themeli, Amiet Chhatta, Hester Boersma, Henk Jan Prins, Martijn Cordes, Edwin de Wilt, Aïda Shahrabi Farahani, Bart Vandekerckhove, Mirjam van der Burg, Rob C. Hoeben, Frank J.T. Staal, Harald M.M. Mikkers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


RAG2 severe combined immune deficiency (RAG2-SCID) is a lethal disorder caused by the absence of functional T and B cells due to a differentiation block. Here, we generated induced pluripotent stem cells (iPSCs) from a RAG2-SCID patient to study the nature of the T cell developmental blockade. We observed a strongly reduced capacity to differentiate at every investigated stage of T cell development, from early CD7CD5 to CD4+CD8+. The impaired differentiation was accompanied by an increase in CD7CD56+CD33+ natural killer (NK) cell-like cells. T cell receptor D rearrangements were completely absent in RAG2SCID cells, whereas the rare T cell receptor B rearrangements were likely the result of illegitimate rearrangements. Repair of RAG2 restored the capacity to induce T cell receptor rearrangements, normalized T cell development, and corrected the NK cell-like phenotype. In conclusion, we succeeded in generating an iPSC-based RAG2-SCID model, which enabled the identification of previously unrecognized disorder-related T cell developmental roadblocks.

Original languageEnglish
Pages (from-to)300-311
Number of pages12
JournalStem Cell Reports
Issue number2
Publication statusPublished - 11 Feb 2020

Cite this