title: A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells.
abstract: The role of forkhead box P3 (FOXP3) is well-established in T-regulatory cells, but the function of transient FOXP3 expression in activated human conventional T (Tconv) cells is unknown. In the present study, we used 2 approaches to determine the role of FOXP3 in human Tconv cells. First, we obtained Tconv clones from a female subject who is hemizygous for a null mutation in FOXP3, allowing the comparison of autologous T-cell clones that do or do not express FOXP3. Second, we knocked down activation-induced FOXP3 in Tconv cells from healthy donors with small interfering RNAagainst FOXP3. We found that FOXP3-deficient Tconv cells proliferate more and produce more cytokines than wild-type Tconv cells and have differential expression of 274 genes. We also investigated the role of FOXP3 in Th1 and Th17 cells and found that the expression of activation-induced FOXP3 was higher and more sustained in Th17 cells compared with Th1 cells. Knocking down FOXP3 expression in Th17 cells significantly increased the production of IFN-γ and decreased the expression of CCR4, but had no effect on IL-17 expression. These data reveal a novel function of FOXP3 in Tconv cells and suggest that expression of this protein is important in the function of multiple CD4(+) T-cell lineages.
authors.affiliation: Department of Surgery, University of British Columbia and Child and Family Research Institute, Vancouver, BC, Canada.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: McMurchy
authors.forename: Jana
authors.initials: J
authors.lastname: Gillies
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Gizzi
authors.forename: Michela
authors.initials: M
authors.lastname: Riba
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Manteiga
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.forename: Dejan
authors.initials: D
authors.lastname: Lazarevic
authors.forename: Sara
authors.initials: S
authors.lastname: Di Nunzio
authors.forename: Ignazio S
authors.initials: IS
authors.lastname: Piras
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bulfone
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D002999:Clone Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D034741:RNA, Small Interfering; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism / Q000502:physiology*; D058504:Th17 Cells / Q000378:metabolism / Q000502:physiology*; D059467:Transcriptome
chemical_list: C515354:CCR4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508594:IL2 protein, human; D007376:Interleukin-2; D034741:RNA, Small Interfering; D054398:Receptors, CCR4; D007371:Interferon-gamma