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

Chandran PA, Keller A, Weinmann L, Seida AA, Braun M, Andreev K, Fischer B, Horn E, Schwinn S, Junker M, Houben R, Dombrowski Y, Dietl J, Finotto S, Woelfl M, Meister G, Wischhusen J (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Journal of Leukocyte Biology Society for Leukocyte Biology

Publisher: Society for Leukocyte Biology

Book Volume: 96

Pages Range: 633-45

Journal Issue: 4

DOI: 10.1189/jlb.3A0114-025R

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 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-? 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.

Authors with CRIS profile

Katerina Andreev Professur für Experimentelle Immuntherapie Susetta Neurath-Finotto Department of Molecular Pneumology

Involved external institutions

Julius-Maximilians-Universität Würzburg DE Germany (DE) Universität des Saarlandes (UdS) DE Germany (DE) Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry DE Germany (DE)

How to cite

APA:

Chandran, P.A., Keller, A., Weinmann, L., Seida, A.A., Braun, M., Andreev, K.,... Wischhusen, J. (2014). The TGF-?-inducible miR-23a cluster attenuates IFN-? levels and antigen-specific cytotoxicity in human CD8? T cells. Journal of Leukocyte Biology, 96(4), 633-45. https://doi.org/10.1189/jlb.3A0114-025R

MLA:

Chandran, P. Anoop, et al. "The TGF-?-inducible miR-23a cluster attenuates IFN-? levels and antigen-specific cytotoxicity in human CD8? T cells." Journal of Leukocyte Biology 96.4 (2014): 633-45.

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