miR-17-92 expression in differentiated T cells - implications for cancer immunotherapy
| Autor: | Ryo Ueda, Heather A. McDonald, Todd A. Reinhart, Francesco M. Marincola, Ena Wang, Michael T. Lotze, Gary Kohanbash, Jeremy J. Martinson, Mitsugu Fujita, Hideho Okada, Aki Hoji, Kotaro Sasaki |
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| Jazyk: | angličtina |
| Předmět: |
lcsh:Medicine
Mice Transgenic Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Interleukin 21 Interferon-gamma Jurkat Cells Mice 0302 clinical medicine Th2 Cells Neoplasms Cytotoxic T cell Animals Humans IL-2 receptor Antigen-presenting cell 030304 developmental biology Interleukin 3 Medicine(all) 0303 health sciences CD40 Cell Death Biochemistry Genetics and Molecular Biology(all) ZAP70 Research lcsh:R Cell Differentiation General Medicine Th1 Cells Microarray Analysis Molecular biology 3. Good health Mice Inbred C57BL MicroRNAs Cancer research biology.protein Interleukin 12 Interleukin-2 Immunotherapy Interleukin-4 030215 immunology Signal Transduction |
| Zdroj: | Journal of Translational Medicine Journal of Translational Medicine, Vol 8, Iss 1, p 17 (2010) |
| ISSN: | 1479-5876 |
| DOI: | 10.1186/1479-5876-8-17 |
| Popis: | Background Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated. Methods We performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells. Results Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-γ production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD). Conclusion The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy. |
| Databáze: | OpenAIRE |
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