Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3

Jeremy A. Goettel, Subhabrata Biswas, Willem S. Lexmond, Ada Yeste, Laura Passerini, Bonny Patel, Siyoung Yang, Jiusong Sun, Jodie Ouahed, Dror S. Shouval, Katelyn J. McCann, Bruce H. Horwitz, Diane Mathis, Edgar L. Milford, Luigi D. Notarangelo, Maria-Grazia Roncarolo, Edda Fiebiger, Wayne A. Marasco, Rosa Bacchetta, Francisco J. Quintana, Sung-Yun Pai, Aleixo M. Muise and Scott B. Snapper

Key points

  • Improved adaptive immune responses in humanized mice lacking murine MHCII and expressing human HLADR1

  • NSGAboDR1 mice reconstituted with hematopoietic stem cells from a patient with IPEX syndrome develop fatal autoimmunity


Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific "humanized" mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHCII) and instead expresses human MHCII DR1. These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multi-organ involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics.

  • Submitted December 19, 2014.
  • Accepted March 23, 2015.