title: CD4⁺ T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer.
abstract: In humans, mutations in the gene encoding for forkhead box P3 (FOXP3), a critically important transcription factor for CD4⁺CD25⁺ regulatory T (T(reg)) 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 T(reg) 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 T(reg) cells after lentivirus-mediated FOXP3 gene transfer, the resulting CD4(FOXP3) T cell population displays stable phenotype and suppressive function, especially when naïve T cells are converted. We further demonstrate that CD4(FOXP3) 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 T(reg) cell-based therapeutic approach to restore tolerance in IPEX syndrome. IPEX-derived CD4(FOXP3) T cells mirrored T(reg) 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 T(reg) cells and are seminal for future potential application in patients with autoimmune disorders of different origin.
authors: San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan 20132, Italy.
authors: Laura
authors: L
authors: Passerini
authors: Eva
authors: E
authors: Rossi Mel
authors: Claudia
authors: C
authors: Sartirana
authors: Georgia
authors: G
authors: Fousteri
authors: Attilio
authors: A
authors: Bondanza
authors: Luigi
authors: L
authors: Naldini
authors: Maria Grazia
authors: MG
authors: Roncarolo
authors: Rosa
authors: R
authors: Bacchetta
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000151:congenital; D003967:Diarrhea; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018014:Gene Transfer Techniques; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology; D005818:Genetic Engineering; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007154:Immune System Diseases / Q000151:congenital; D007156:Immunologic Memory; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors