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

Stem Cell Reports. 2020 Feb 11;14(2):300-311. doi: 10.1016/j.stemcr.2019.12.010. Epub 2020 Jan 16.


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.

Keywords: CD56(+)CD33(+); NK cells; RAG; SCID; T cell development; disease modeling; iPSC; immunodeficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Cell Differentiation
  • Cell Lineage
  • DNA-Binding Proteins / metabolism*
  • Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
  • Hematopoiesis
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Killer Cells, Natural / immunology
  • Mice, SCID
  • Models, Biological*
  • Severe Combined Immunodeficiency / immunology*
  • Severe Combined Immunodeficiency / pathology*
  • T-Lymphocytes / immunology*


  • Antigens, CD
  • DNA-Binding Proteins
  • V(D)J recombination activating protein 2