title: Wild-type FOXP3 is selectively active in CD4+CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations.
abstract: Forkhead box P3 (FOXP3) is constitutively expressed by CD4(+)CD25(hi) regulatory T cells (nTregs). Mutations of FOXP3 cause a severe autoimmune syndrome known as immune dysregulation polyendocrinopathy enteropathy X-linked, in which nTregs are absent or dysfunctional. Whether FOXP3 is essential for both differentiation and function of human nTreg cells remains to be demonstrated. Because FOXP3 is an X-linked gene subject to X-chromosome inactivation (XCI), we studied 9 healthy female carriers of FOXP3 mutations to investigate the role of wild-type (WT) versus mutated FOXP3 in different cell subsets. Analysis of active WT versus mutated (mut)-FOXP3 allele distribution revealed a random pattern of XCI in peripheral blood lymphocytes and in naive and memory CD4(+)T cells, whereas nTregs expressed only the active WT-FOXP3. These data demonstrate that expression of WT-FOXP3 is indispensable for the presence of a normal nTreg compartment and suggest that FOXP3 is not necessary for effector T-cell differentiation in humans.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 58-20132 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Di Nunzio
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cecconi
authors.forename: Laura
authors.initials: L
authors.lastname: Passerini
authors.forename: Alicia N
authors.initials: AN
authors.lastname: McMurchy
authors.forename: Udo
authors.initials: U
authors.lastname: Baron
authors.forename: Ivana
authors.initials: I
authors.lastname: Turbachova
authors.forename: Silvia
authors.initials: S
authors.lastname: Vignola
authors.forename: Erica
authors.initials: E
authors.lastname: Valencic
authors.forename: Alberto
authors.initials: A
authors.lastname: Tommasini
authors.forename: Anne
authors.initials: A
authors.lastname: Junker
authors.forename: Giantonio
authors.initials: G
authors.lastname: Cazzola
authors.forename: Sven
authors.initials: S
authors.lastname: Olek
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
authors.forename: Lucia
authors.initials: L
authors.lastname: Perroni
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D049951:X Chromosome Inactivation
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors