Ectopic FOXP3 Expression Preserves Primitive Features Of Human Hematopoietic Stem Cells While Impairing Functional T Cell Differentiation

FOXP3 is the transcription factor ruling regulatory T cell function and maintenance of peripheral immune tolerance, and mutations in its coding gene causes IPEX autoimmune syndrome. FOXP3 is also a cell-cycle inhibitor and onco-suppressor in different cell types. In this work, we investigate the eff...

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Bibliographic Details
Published in:Scientific reports 2017-11, Vol.7 (1), p.15820-10, Article 15820
Main Authors: Santoni de Sio, F. R., Passerini, L., Valente, M. M., Russo, F., Naldini, L., Roncarolo, M. G., Bacchetta, R.
Format: Article
Language:English
Subjects:
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Cell differentiation
Foxp3 protein
Gene therapy
Hematopoietic stem cells
Humanities and Social Sciences
Immunodeficiency
Immunological tolerance
Lymphocytes T
multidisciplinary
Rodents
Science
Science (multidisciplinary)
Stem cell transplantation
Stem cells
Therapeutic applications
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Summary:FOXP3 is the transcription factor ruling regulatory T cell function and maintenance of peripheral immune tolerance, and mutations in its coding gene causes IPEX autoimmune syndrome. FOXP3 is also a cell-cycle inhibitor and onco-suppressor in different cell types. In this work, we investigate the effect of ectopic FOXP3 expression on HSC differentiation and we challenged this approach as a possible HSC-based gene therapy for IPEX. FOXP3-expressing HSC showed reduced proliferation ability and increased maintenance of primitive markers in vitro in both liquid and OP9-ΔL1 co-cultures. When transplanted into immunodeficient mice, FOXP3-expressing HSC showed significantly enhanced engraftment ability. This was due to a pronounced increase in the frequency of repopulating cells, as assessed by extreme limiting dilution assay. Likely underlying the increased repopulating ability, FOXP3 expressing HSC showed significantly enhanced expression of genes controlling stemness features. However, peripheral T cells developed in the FOXP3-humanized mice were quantitatively reduced and hyporesponsive to cytokine and polyclonal stimulation. Our findings reveal unpredicted effects of FOXP3 in the biology of HSC and may provide new tools to manipulate primitive features in HSC for clinical applications. Moreover, they formally prove the need of preserving endogenous FOXP3 regulation for an HSC-based gene therapy approach for IPEX syndrome.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-15689-8