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 CD7−CD5− to CD4+CD8+. The impaired differentiation was accompanied by an increase in CD7−CD56+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.In this article, Mikkers and colleagues model RAG2-SCID using iPSCs and show that the capacity of RAG2-SCID cells to go through T cell development is hampered at multiple transitions from the earliest stage onwards. As a consequence RAG2 mutant cells generate more CD7−CD56+ CD33+ cells with NK cell properties.

CD56+CD33+, disease modeling, immunodeficiency, iPSC, NK cells, RAG, SCID, T cell development
dx.doi.org/10.1016/j.stemcr.2019.12.010, hdl.handle.net/1765/124420
Stem Cell Reports
Department of Immunology

Themeli, M. (Maria), Chhatta, A. (Amiet), Boersma, H. (Hester), Prins, H.-J, Cordes, M. (Martijn), de Wilt, E, … Mikkers, H. (2020). iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests. Stem Cell Reports, 14(2), 300–311. doi:10.1016/j.stemcr.2019.12.010