Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation.
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.
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Related Subject Headings
- Th1 Cells
- T-Lymphocytes, Regulatory
- Skin Neoplasms
- Receptors, Transforming Growth Factor beta
- Receptor, Transforming Growth Factor-beta Type II
- Protein Serine-Threonine Kinases
- Multigene Family
- MicroRNAs
- Mice, Knockout
- Mice, Inbred C57BL
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Th1 Cells
- T-Lymphocytes, Regulatory
- Skin Neoplasms
- Receptors, Transforming Growth Factor beta
- Receptor, Transforming Growth Factor-beta Type II
- Protein Serine-Threonine Kinases
- Multigene Family
- MicroRNAs
- Mice, Knockout
- Mice, Inbred C57BL