Expression of miRNAs miR-133b and miR-206 in the Il17a/f locus is co-regulated with IL-17 production in αβ and γδ T cells

• Published in: PloS one Vol. 6; no. 5; p. e20171
• Main Authors: Haas, Jan D, Nistala, Kiran, Petermann, Franziska, Saran, Namita, Chennupati, Vijaykumar, Schmitz, Susanne, Korn, Thomas, Wedderburn, Lucy R, Förster, Reinhold, Krueger, Andreas, Prinz, Immo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2011; Public Library of Science (PLoS)
• Subjects: Animals; Bacterial infections; Base Sequence; Bioassays; Biology; Biomarkers; CCR6 protein; CD4 antigen; Cell differentiation; Cell Differentiation - genetics; Cell Polarity - genetics; Cells, Cultured; Childrens health; Cloning; Cytokines; Differentiation (biology); Epigenetics; Gene expression; Gene Expression Regulation; Gene regulation; Genetic Loci; Genomes; Helper cells; Humans; Immunology; Inbreeding; Interleukin 1; Interleukin 17; Interleukin 21; Interleukin 23; Interleukin 6; Interleukin-17 - biosynthesis; Interleukin-17 - genetics; Interleukin-23 - metabolism; Loci; Lymphocytes; Lymphocytes T; Medical schools; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular Sequence Data; Muscular dystrophy; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Rheumatology; Signaling; Synteny; Synteny - genetics; Th17 Cells - cytology; Th17 Cells - metabolism; Transcription; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020171

Differentiation of T helper 17 cells (Th17) is a multistep process that involves the cytokines IL-6, TGF-β, and IL-23 as well as IL-1β, IL-21, and TNF-α. Thereby, robust induction of the capacity to produce IL-17 involves epigenetic modifications of the syntenic Il17a/f locus. Using inbred mouse strains, we identified co-regulation of gene transcription at the Il17a/f locus with the nearby microRNAs miR-133b and miR-206 that are clustered approximately 45 kb upstream of Il17a/f. Expression of these microRNAs was specific for Th17 as compared to other CD4(+) T cell subsets and this was equally valid for in vitro polarized and ex vivo derived cells. From all factors analyzed, IL-23 was the most important cytokine for the in vitro induction of miR-133b and miR-206 in naive CD4(+) T cells of wild type mice. However, analysis of IL-23R deficient mice revealed that IL-23R signaling was not essential for the induction of miR-133b and miR-206. Importantly, we found a similar co-regulation in CCR6(+) and other γδ T cell subsets that are predisposed to production of IL-17. Taken together, we discovered a novel feature of T cell differentiation towards an IL-17-producing phenotype that is shared between αβ and γδ T cells. Notably, the specific co-regulation of miR-133b and miR-206 with the Il17a/f locus also extended to human Th17 cells. This qualifies expression of miR-133b and miR-206 in T cells as novel biomarkers for Th17-type immune reactions.