Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation

Blood. 2011 Nov 17;118(20):5487-97. doi: 10.1182/blood-2011-05-355644. Epub 2011 Oct 4.


Mir-17-92 encodes 6 miRNAs inside a single polycistronic transcript, the proper expression of which is critical for early B-cell development and lymphocyte homeostasis. However, during the T-cell antigen response, the physiologic function of endogenous miR-17-92 and the roles of the individual miRNAs remain elusive. In the present study, we functionally dissected the miR-17-92 cluster and revealed that miR-17 and miR-19b are the key players controlling Th1 responses through multiple coordinated biologic processes. These include: promoting proliferation, protecting cells from activation-induced cell death, supporting IFN-γ production, and suppressing inducible regulatory T-cell differentiation. Mechanistically, we identified Pten (phosphatase and tensin homolog) as the functionally important target of miR-19b, whereas the function of miR-17 is mediated by TGFβRII and the novel target CREB1. Because of its vigorous control over the Th1 cell-inducible regulatory T cell balance, the loss of miR-17-92 in CD4 T cells results in tumor evasion. Our results suggest that miR-19b and miR-17 could be harnessed to enhance the efficacy of T cell-based tumor therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / genetics
  • Adaptive Immunity / immunology
  • Animals
  • Cell Differentiation / immunology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Disease Models, Animal
  • Immunotherapy / methods
  • Interferon-gamma / immunology
  • Melanoma / immunology
  • Melanoma / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / immunology
  • Multigene Family
  • Protein Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • Skin Neoplasms / immunology
  • Skin Neoplasms / therapy
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / physiology*
  • Th1 Cells / cytology*
  • Th1 Cells / physiology*


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • MIRN19 microRNA, mouse
  • MicroRNAs
  • Mirn17 microRNA, mouse
  • Receptors, Transforming Growth Factor beta
  • Interferon-gamma
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II