title: Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function.
abstract: Lethal-7 (let-7) microRNAs (miRNAs) are the most abundant miRNAs in the genome, but their role in developing thymocytes is unclear. We found that let-7 miRNAs targeted Zbtb16 mRNA, which encodes the lineage-specific transcription factor PLZF, to post-transcriptionally regulate PLZF expression and thereby the effector functions of natural killer T cells (NKT cells). Dynamic upregulation of let-7 miRNAs during the development of NKT thymocytes downregulated PLZF expression and directed their terminal differentiation into interferon-γ (IFN-γ)-producing NKT1 cells. Without upregulation of let-7 miRNAs, NKT thymocytes maintained high PLZF expression and terminally differentiated into interleukin 4 (IL-4)-producing NKT2 cells or IL-17-producing NKT17 cells. Upregulation of let-7 miRNAs in developing NKT thymocytes was signaled by IL-15, vitamin D and retinoic acid. Such targeting of a lineage-specific transcription factor by miRNA represents a previously unknown level of developmental regulation in the thymus.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Leonid A
authors.initials: LA
authors.lastname: Pobezinsky
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Etzensperger
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Jeurling
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Amala
authors.initials: A
authors.lastname: Alag
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Tejas
authors.initials: T
authors.lastname: Kadakia
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Tom M
authors.initials: TM
authors.lastname: McCaughtry
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Motoko Y
authors.initials: MY
authors.lastname: Kimura
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Susan O
authors.initials: SO
authors.lastname: Sharrow
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Terry I
authors.initials: TI
authors.lastname: Guinter
authors.affiliation: SAIC-Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Singer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000502:physiology*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D060168:Thymocytes / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism; D015854:Up-Regulation; D014807:Vitamin D / Q000378:metabolism
chemical_list: D016207:Cytokines; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C513267:Zbtb16 protein, mouse; C542687:mirnlet7 microRNA, mouse; D014807:Vitamin D; D014212:Tretinoin
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