The TGF-β-inducible miR-23a cluster attenuates IFN-γ levels and antigen-specific cytotoxicity in human CD8+ T cells

P Anoop Chandran, Andreas Keller, Lasse Weinmann, Ahmed Adel Seida, Matthias Braun, Katerina Andreev, Birgitt Fischer, Evi Horn, Stefanie Schwinn, Markus Junker, Roland Houben, Yvonne Dombrowski, Johannes Dietl, Susetta Finotto, Matthias Wölfl, Gunter Meister, Jörg Wischhusen

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31 Citations (Scopus)

Abstract

Cytokine secretion and degranulation represent key components of CD8(+) T-cell cytotoxicity. While transcriptional blockade of IFN-γ and inhibition of degranulation by TGF-β are well established, we wondered whether TGF-β 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-β promotes expression of the miR-23a cluster in human CD8(+) T cells. Likewise, TGF-β 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-β type II receptor. Reporter gene assays including site mutations confirmed that miR-23a specifically targets the 3'UTR of CD107a/LAMP1 mRNA, whereas the further miRNAs expressed in this cluster-namely, miR-27a and -24-target the 3'UTR of IFN-γ mRNA. Upon modulation of the miR-23a cluster by the respective miRNA antagomirs and mimics, we observed significant changes in IFN-γ 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-β, but also exerts a suppressive effect on CD8(+) T-cell effector functions, even in the absence of TGF-β signaling.

Original languageEnglish
Pages (from-to)633-645
Number of pages13
JournalJournal of Leukocyte Biology
Volume96
Issue number4
Early online date16 Jul 2014
DOIs
Publication statusPublished - Oct 2014

Bibliographical note

© 2014 Society for Leukocyte Biology.

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    Chandran, P. A., Keller, A., Weinmann, L., Adel Seida, A., Braun, M., Andreev, K., Fischer, B., Horn, E., Schwinn, S., Junker, M., Houben, R., Dombrowski, Y., Dietl, J., Finotto, S., Wölfl, M., Meister, G., & Wischhusen, J. (2014). The TGF-β-inducible miR-23a cluster attenuates IFN-γ levels and antigen-specific cytotoxicity in human CD8+ T cells. Journal of Leukocyte Biology, 96(4), 633-645. https://doi.org/10.1189/jlb.3A0114-025R