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.

RAG2严重的联合免疫缺陷病（RAG2-SCID）是一种致命的疾病，由于分化障碍导致功能性T细胞和B细胞缺失。在这里，我们从RAG2-SCID患者中产生了诱导性多能干细胞（iPSC），以研究T细胞发育性阻断的本质。我们在T细胞发育的各个阶段的研究中观察到的强烈能力降低区别开来，从早期CD7 ^- CD5 ^-到CD4 ⁺ CD8 ⁺。分化受损伴随着CD7 ^- CD56 ⁺ CD33 ⁺自然杀伤（NK）细胞样细胞的增加。RAG2SCID中完全不存在T细胞受体D重排细胞，而罕见的T细胞受体B重排很可能是非法重排的结果。修复RAG2恢复了诱导T细胞受体重排，正常化T细胞发育并纠正NK细胞样表型的能力。总之，我们成功地生成了基于iPSC的RAG2-SCID模型，该模型能够识别先前无法识别的与疾病相关的T细胞发育障碍。