Data from our group and others have demonstrated that tumor-derived factors directly skew T-cell differentiation from an effective tumor fighting Th1 state to a less effective Th2 state, allowing for tumor growth. Why the Th1 response is more effective is largely still unknown. The recently discovered microRNAs (miRNAs) are a large family of small regulatory RNAs that control diverse aspects of cell functions such as cell proliferation, apoptosis, development, differentiation and immune regulation. We thereby sought to examine miRNAs differentially expressed in Th1 and Th2 cells in an effort to better understand the enhanced ability of Th1 cells in tumor immunity. MicroRNA microarray analyses revealed that the miR-17-92 cluster of microRNAs (miR-17-92) is consistently over-expressed in murine Th1 cells compared to Th2 cells. Quantitative RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Furthermore, disruption of IL-4 signaling through either IL-4 neutralizing antibody or knockout of STAT6 reversed the miR-17-92 cluster suppression in Th2 cells. MiR-17-92 expression correlated with differential proliferation capacity as Th1 cells proliferated at higher levels than Th2 cells, dependent on IL-4 and STAT6. Th1 cells consistently expressed lower levels of anti-proliferative transcription factors E2F1 and E2F2, which are the known targets of miR-17-92. Collectively, our data suggests that the Th2 skewing tumor microenvironment can induce the down-regulation of miR-17-92 expression in CD4+T cells, thereby diminishing the effective proliferation of tumor-specific T cells and tumor destruction. This has significant public health relevance as we propose that therapy targeting miR-17-92 cluster may provide enhanced T-cell function and prevent tumor growth.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07282009-112806 |
| Date | 29 September 2009 |
| Creators | Kohanbash, Gary |
| Contributors | Jeremy Martinson, Hideho Okada, Todd Reinhart |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-07282009-112806/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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