Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function

Nat Immunol. 2015 May;16(5):517-24. doi: 10.1038/ni.3146. Epub 2015 Apr 6.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Cytokines / metabolism*
  • Cytotoxicity, Immunologic / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Natural Killer T-Cells / physiology*
  • Promyelocytic Leukemia Zinc Finger Protein
  • Protein Binding
  • RNA Processing, Post-Transcriptional
  • Thymocytes / physiology*
  • Tretinoin / metabolism
  • Up-Regulation
  • Vitamin D / metabolism


  • Cytokines
  • Kruppel-Like Transcription Factors
  • MicroRNAs
  • Promyelocytic Leukemia Zinc Finger Protein
  • Zbtb16 protein, mouse
  • mirnlet7 microRNA, mouse
  • Vitamin D
  • Tretinoin