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The TGF-ß-inducible miR-23a cluster attenuates IFN-γ levels and antigen-specific cytotoxicity in human CD8⁺ T cells.
Chandran, P Anoop; Keller, Andreas; Weinmann, Lasse; Seida, Ahmed Adel; Braun, Matthias; Andreev, Katerina; Fischer, Birgitt; Horn, Evi; Schwinn, Stefanie; Junker, Markus; Houben, Roland; Dombrowski, Yvonne; Dietl, Johannes; Finotto, Susetta; Wölfl, Matthias; Meister, Gunter; Wischhusen, Jörg.
Afiliación
  • Chandran PA; Graduate School of Life Sciences (GSLS), University of Würzburg, Germany; Department of Obstetrics and Gynecology.
  • Keller A; Chair for Clinical Bioinformatics, Saarland University, Saarbrücken, Germany;
  • Weinmann L; Max Planck Institute of Biochemistry, Martinsried, Germany;
  • Seida AA; Department of Obstetrics and Gynecology, Interdisciplinary Center for Clinical Research.
  • Braun M; Pediatric Hematology, Oncology, and Stem Cell Transplantation, Children's Hospital.
  • Andreev K; Laboratory of Cellular and Molecular Lung Immunology, Institute of Molecular Pneumology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; and.
  • Fischer B; Department of Obstetrics and Gynecology.
  • Horn E; Department of Obstetrics and Gynecology.
  • Schwinn S; Pediatric Hematology, Oncology, and Stem Cell Transplantation, Children's Hospital.
  • Junker M; Department of Obstetrics and Gynecology, Interdisciplinary Center for Clinical Research.
  • Houben R; Department of Dermatology, University of Würzburg Medical School, Würzburg, Germany;
  • Dombrowski Y; Department of Obstetrics and Gynecology, Interdisciplinary Center for Clinical Research.
  • Dietl J; Department of Obstetrics and Gynecology.
  • Finotto S; Laboratory of Cellular and Molecular Lung Immunology, Institute of Molecular Pneumology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; and.
  • Wölfl M; Pediatric Hematology, Oncology, and Stem Cell Transplantation, Children's Hospital.
  • Meister G; Max Planck Institute of Biochemistry, Martinsried, Germany; Department of Biochemistry, University of Regensburg, Germany.
  • Wischhusen J; Department of Obstetrics and Gynecology, Interdisciplinary Center for Clinical Research, wischhusen_j@ukw.de.
J Leukoc Biol ; 96(4): 633-45, 2014 Oct.
Article en En | MEDLINE | ID: mdl-25030422
Cytokine secretion and degranulation represent key components of CD8(+) T-cell cytotoxicity. While transcriptional blockade of IFN-γ and inhibition of degranulation by TGF-ß are well established, we wondered whether TGF-ß 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-ß promotes expression of the miR-23a cluster in human CD8(+) T cells. Likewise, TGF-ß 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-ß 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-ß, but also exerts a suppressive effect on CD8(+) T-cell effector functions, even in the absence of TGF-ß signaling.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta / Interferón gamma / Linfocitos T CD8-positivos / Epítopos de Linfocito T / Citotoxicidad Inmunológica / MicroARNs Límite: Humans Idioma: En Revista: J Leukoc Biol Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta / Interferón gamma / Linfocitos T CD8-positivos / Epítopos de Linfocito T / Citotoxicidad Inmunológica / MicroARNs Límite: Humans Idioma: En Revista: J Leukoc Biol Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido