In humans, mutations in the gene encoding for forkhead box P3 (FOXP3), a critically important transcription factor for CD4+CD25+ regulatory T (Treg) cell function, lead to a life-threatening systemic poly-autoimmune disease, known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Severe autoimmunity results from the inborn dysfunction and instability of FOXP3-mutated Treg cells. Hematopoietic stem cell transplantation is the only current curative option for affected patients. We show here that when CD4+ T cells are converted into Treg cells after lentivirus-mediated FOXP3 gene transfer, the resulting CD4FOXP3 T cell population displays stable phenotype and suppressive function, especially when naïve T cells are converted. We further demonstrate that CD4FOXP3 T cells are stable in inflammatory conditions not only in vitro but also in vivo in a model of xenogeneic graft-versus-host disease. We therefore applied this FOXP3 gene transfer strategy for the development of a Treg cell-based therapeutic approach to restore tolerance in IPEX syndrome. IPEX-derived CD4FOXP3 T cells mirrored Treg cells from healthy donors in terms of cellular markers, anergic phenotype, cytokine production, and suppressive function. These findings pave the way for the treatment of IPEX patients by adoptive cell therapy with genetically engineered Treg cells and are seminal for future potential application in patients with autoimmune disorders of different origin.
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