title: miR-23∼27∼24 clusters control effector T cell differentiation and function.
abstract: Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR-23∼27∼24 clusters regulate multiple aspects of T cell biology, particularly helper T (Th) 2 immunity. Low expression of this miRNA family confers proper effector T cell function at both physiological and pathological settings. Further studies in T cells with exaggerated regulation by individual members of the miR-23∼27∼24 clusters revealed that miR-24 and miR-27 collaboratively limit Th2 responses through targeting IL-4 and GATA3 in both direct and indirect manners. Intriguingly, although overexpression of the entire miR-23 cluster also negatively impacts other Th lineages, enforced expression of miR-24, in contrast to miR-23 and miR-27, actually promotes the differentiation of Th1, Th17, and induced regulatory T cells, implying that under certain conditions, miRNA families can fine tune the biological effects of their regulation by having individual members antagonize rather than cooperate with each other. Together, our results identify a miRNA family with important immunological roles and suggest that tight regulation of miR-23∼27∼24 clusters in T cells is required to maintain optimal effector function and to prevent aberrant immune responses.
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Sunglim
authors.initials: S
authors.lastname: Cho
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093 Department of Microbiology and Immunology, College of Medicine, Chang Gung University, 333 Taoyuan, Taiwan.
authors.forename: Cheng-Jang
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Leilani O
authors.initials: LO
authors.lastname: Cruz
authors.affiliation: Toyota Technological Institute at Chicago, Chicago, IL 60637.
authors.forename: Aly Azeem
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Ling-Li
authors.initials: LL
authors.lastname: Lin
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Duc T
authors.initials: DT
authors.lastname: Nguyen
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Hyang-Mi
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Chang Gung University, 333 Taoyuan, Taiwan.
authors.forename: Ming-Ling
authors.initials: ML
authors.lastname: Kuo
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.affiliation: Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 lifanlu@ucsd.edu.
authors.forename: Li-Fan
authors.initials: LF
authors.lastname: Lu
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology*; D005810:Multigene Family; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; C529080:Mirn24 microRNA, mouse; C540674:Mirn27 microRNA, mouse; D015847:Interleukin-4
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