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The TGF-β-inducible miR-23a Cluster Attenuates IFN-γ Levels and Antigen-Specific Cytotoxicity in Human CD8⁺ T Cells

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, etc.

J Leukoc Biol. 2014 Oct;96(4):633-45.

PMID: 25030422

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413179	LAMP1/CD107a human			Price

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