Wild-type FOXP3 is selectively active in CD4+CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations.
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.
Di Nunzio
Sara
S
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.
Cecconi
Massimiliano
M
Passerini
Laura
L
McMurchy
Alicia N
AN
Baron
Udo
U
Turbachova
Ivana
I
Vignola
Silvia
S
Valencic
Erica
E
Tommasini
Alberto
A
Junker
Anne
A
Cazzola
Giantonio
G
Olek
Sven
S
Levings
Megan K
MK
Perroni
Lucia
L
Roncarolo
Maria Grazia
MG
Bacchetta
Rosa
R
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
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors