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. QuintanaSung Yun Pai, Christoph Klein, Aleixo M. Muise, Scott B. Snapper*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-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 multiorgan 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.

Original languageEnglish
Pages (from-to)3886-3895
Number of pages10
Issue number25
StatePublished - 18 Jun 2015
Externally publishedYes


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