title: Genome-wide identification of human FOXP3 target genes in natural regulatory T cells.
abstract: The transcription factor FOXP3 is essential for the formation and function of regulatory T cells (Tregs), and Tregs are essential for maintaining immune homeostasis and tolerance. This is demonstrated by a lethal autoimmune defect in mice lacking Foxp3 and in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome patients. However, little is known about the molecular basis of human FOXP3 function or the relationship between direct and indirect targets of FOXP3 in human Tregs. To investigate this, we have performed a comprehensive genome-wide analysis for human FOXP3 target genes from cord blood Tregs using chromatin immunoprecipitation array profiling and expression profiling. We have identified 5579 human FOXP3 target genes and derived a core Treg gene signature conserved across species using mouse chromatin immunoprecipitation data sets. A total of 739 of the 5579 FOXP3 target genes were differentially regulated in Tregs compared with Th cells, thus allowing the identification of a number of pathways and biological functions overrepresented in Tregs. We have identified gene families including cell surface molecules and microRNAs that are differentially expressed in FOXP3(+) Tregs. In particular, we have identified a novel role for peptidase inhibitor 16, which is expressed on the cell surface of >80% of resting human CD25(+)FOXP3(+) Tregs, suggesting that in conjunction with CD25 peptidase inhibitor 16 may be a surrogate surface marker for Tregs with potential clinical application.
authors.affiliation: Molecular Immunology Laboratory, Women's and Children's Health Research Institute, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sadlon
authors.forename: Bridget G
authors.initials: BG
authors.lastname: Wilkinson
authors.forename: Stephen
authors.initials: S
authors.lastname: Pederson
authors.forename: Cheryl Y
authors.initials: CY
authors.lastname: Brown
authors.forename: Suzanne
authors.initials: S
authors.lastname: Bresatz
authors.forename: Tessa
authors.initials: T
authors.lastname: Gargett
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Melville
authors.forename: Kaimen
authors.initials: K
authors.lastname: Peng
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
authors.forename: Gary G
authors.initials: GG
authors.lastname: Glonek
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.forename: Heddy
authors.initials: H
authors.lastname: Zola
authors.forename: M Frances
authors.initials: MF
authors.lastname: Shannon
authors.forename: Simon C
authors.initials: SC
authors.lastname: Barry
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D049109:Cell Proliferation; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors