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

• Published in: The Journal of biological chemistry Vol. 287; no. 13; pp. 9910 - 9922
• Main Authors: Fayyad-Kazan, Hussein, Rouas, Redouane, Fayyad-Kazan, Mohammad, Badran, Rabih, El Zein, Nabil, Lewalle, Philippe, Najar, Medhi, Hamade, Eva, Jebbawi, Fadi, Merimi, Makram, Romero, Pedro, Burny, Arsène, Badran, Bassam, Martiat, Philippe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.03.2012; American Society for Biochemistry and Molecular Biology
• Subjects: 3' Untranslated Regions - physiology; Adaptive Tregs; Adult; Cell Biology; CTLA-4; CTLA-4 Antigen - biosynthesis; CTLA-4 Antigen - genetics; Female; Forkhead Transcription Factors - biosynthesis; Forkhead Transcription Factors - genetics; FOXP3; Gene Expression Profiling; Gene Expression Regulation - physiology; Gene Regulation; HEK293 Cells; HeLa Cells; Human Genetics; Humans; Male; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; T Cell Biology; T-Lymphocytes, Regulatory - metabolism; Tolerance; Gene Regulation; Human Genetics; MicroRNA; Tolerance; CTLA-4; T Cell Biology; Adaptive Tregs; FOXP3
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.337154

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. Regulatory T cells are a subset of T cells with immunosuppressive properties, crucial for immune tolerance, which are also associated with cancer development. The human circulating CD4+ Treg microRNA signature was identified. Differentially expressed microRNAs from the Treg miR signature directly and indirectly regulate crucial Treg genes (FOXP3 and CTLA-4). Identifying novel regulatory mechanisms of crucial Treg genes expression provides better insight into their biology and offers potential new targets for immunomodulatory therapies.