title: MicroRNA profile of circulating CD4-positive regulatory T cells in human adults and impact of differentially expressed microRNAs on expression of two genes essential to their function.
abstract: Regulatory T cells (Tregs) are characterized by a high expression of IL-2 receptor α chain (CD25) and of forkhead box P3 (FOXP3), the latter being essential for their development and function. Another major player in the regulatory function is the cytotoxic T-lymphocyte associated molecule-4 (CTLA-4) that inhibits cytotoxic responses. However, the regulation of CTLA-4 expression remains less well explored. We therefore studied the microRNA signature of circulating CD4(+) Tregs isolated from adult healthy donors and identified a signature composed of 15 differentially expressed microRNAs. Among those, miR-24, miR-145, and miR-210 were down-regulated in Tregs compared with controls and were found to have potential target sites in the 3'-UTR of FOXP3 and CTLA-4; miR-24 and miR-210 negatively regulated FOXP3 expression by directly binding to their two target sites in its 3'-UTR. On the other hand, miR-95, which is highly expressed in adult peripheral blood Tregs, positively regulated FOXP3 expression via an indirect mechanism yet to be identified. Finally, we showed that miR-145 negatively regulated CTLA-4 expression in human CD4(+) adult peripheral blood Tregs by binding to its target site in CTLA-4 transcript 3'-UTR. To our knowledge, this is the first identification of a human adult peripheral blood CD4(+) Treg microRNA signature. Moreover, unveiling one mechanism regulating CTLA-4 expression is novel and may lead to a better understanding of the regulation of this crucial gene.
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Hussein
authors.initials: H
authors.lastname: Fayyad-Kazan
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Redouane
authors.initials: R
authors.lastname: Rouas
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fayyad-Kazan
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Rabih
authors.initials: R
authors.lastname: Badran
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Nabil
authors.initials: N
authors.lastname: El Zein
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lewalle
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Medhi
authors.initials: M
authors.lastname: Najar
authors.affiliation: Department of Biochemistry, Laboratory of Immunology, EDST-PRASE, Lebanese University, Faculty of Sciences, Hadath-Beirut, Lebanon, and.
authors.forename: Eva
authors.initials: E
authors.lastname: Hamade
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Fadi
authors.initials: F
authors.lastname: Jebbawi
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Makram
authors.initials: M
authors.lastname: Merimi
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, 4 Avenue Pierre-Decker, 1005 Lausanne, Switzerland.
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Arsène
authors.initials: A
authors.lastname: Burny
authors.affiliation: Department of Biochemistry, Laboratory of Immunology, EDST-PRASE, Lebanese University, Faculty of Sciences, Hadath-Beirut, Lebanon, and.
authors.forename: Bassam
authors.initials: B
authors.lastname: Badran
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium;. Electronic address: pmartiat@ulb.ac.be.
authors.forename: Philippe
authors.initials: P
authors.lastname: Martiat
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology*; D000328:Adult; D060908:CTLA-4 Antigen / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D035683:MicroRNAs