Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation.
Blood, 2011/11/17;118(20):5487-97.
Jiang S[1], Li C, Olive V, Lykken E, Feng F, Sevilla J, Wan Y, He L, Li QJ
Affiliations
PMID: 21972292DOI: 10.1182/blood-2011-05-355644
Impact factor: 25.476
Abstract
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.
MeSH terms
Adaptive Immunity; Animals; Cell Differentiation; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Immunotherapy; Interferon-gamma; Melanoma; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Multigene Family; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Skin Neoplasms; T-Lymphocytes, Regulatory; Th1 Cells
More resources
Full text:
Europe PubMed Central; PubMed Central
EndNote: Download