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The TGF-beta-inducible miR-23a cluster attenuates IFN-gamma levels and antigen-specific cytotoxicity in human CD8(+) T cells

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Weinmann,  Lasse
Former Research Groups, Max Planck Institute of Biochemistry, Max Planck Society;

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Meister,  Gunter
Former Research Groups, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Chandran, P. A., Keller, A., Weinmann, L., Seida, A. A., Braun, M., Andreev, K., et al. (2014). The TGF-beta-inducible miR-23a cluster attenuates IFN-gamma levels and antigen-specific cytotoxicity in human CD8(+) T cells. JOURNAL OF LEUKOCYTE BIOLOGY, 96(4), 633-645. doi:10.1189/jlb.3A0114-025R.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0023-FD0A-E
Abstract
Cytokine secretion and degranulation represent key components of CD8(+) T-cell cytotoxicity. While transcriptional blockade of IFN- and inhibition of degranulation by TGF- are well established, we wondered whether TGF- could also induce immune-regulatory miRNAs in human CD8(+) T cells. We used miRNA microarrays and high-throughput sequencing in combination with qRT-PCR and found that TGF- promotes expression of the miR-23a cluster in human CD8(+) T cells. Likewise, TGF- up-regulated expression of the cluster in CD8(+) T cells from wild-type mice, but not in cells from mice with tissue-specific expression of a dominant-negative TGF- type II receptor. Reporter gene assays including site mutations confirmed that miR-23a specifically targets the 3UTR of CD107a/LAMP1 mRNA, whereas the further miRNAs expressed in this clusternamely, miR-27a and -24target the 3UTR of IFN- mRNA. Upon modulation of the miR-23a cluster by the respective miRNA antagomirs and mimics, we observed significant changes in IFN- expression, but only slight effects on CD107a/LAMP1 expression. Still, overexpression of the cluster attenuated the cytotoxic activity of antigen-specific CD8(+) T cells. These functional data thus reveal that the miR-23a cluster not only is induced by TGF-, but also exerts a suppressive effect on CD8(+) T-cell effector functions, even in the absence of TGF- signaling.