The TGF-β-inducible miR-23a cluster attenuates IFN-γ levels and antigen-specific cytotoxicity in human CD8⁺ T cells.
J Leukoc Biol, 2014/10;96(4):633-45.
Chandran PA[1], Keller A[2], Weinmann L[3], Seida AA[4], Braun M[5], Andreev K[6], Fischer B[7], Horn E[7], Schwinn S[5], Junker M[4], Houben R[8], Dombrowski Y[4], Dietl J[7], Finotto S[6], Wölfl M[5], Meister G[9], Wischhusen J[10]
Affiliations
PMID: 25030422DOI: 10.1189/jlb.3A0114-025R
Impact factor: 6.011
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.
Keywords: antigen-specific T cells; miRNA induction; tolerance; tumor targets
MeSH terms
3' Untranslated Regions; Base Sequence; Binding Sites; CD8-Positive T-Lymphocytes; Cell Line; Cells, Cultured; Cytotoxicity, Immunologic; Epitopes, T-Lymphocyte; Gene Expression Regulation; Humans; Interferon-gamma; Lymphocyte Activation; Lysosomal-Associated Membrane Protein 1; MART-1 Antigen; MicroRNAs; Multigene Family; RNA Interference; Transforming Growth Factor beta
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