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The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor

Nature Immunology volume 13, pages 181187 (2012) | Download Citation

Abstract

Thymic output is a dynamic process, with high activity at birth punctuated by transient periods of involution during infection. Interferon-α (IFN-α) is a critical molecular mediator of pathogen-induced thymic involution, yet despite the importance of thymic involution, relatively little is known about the molecular integrators that establish sensitivity. Here we found that the microRNA network dependent on the endoribonuclease Dicer, and specifically microRNA miR-29a, was critical for diminishing the sensitivity of the thymic epithelium to simulated infection signals, protecting the thymus against inappropriate involution. In the absence of Dicer or the miR-29a cluster in the thymic epithelium, expression of the IFN-α receptor by the thymic epithelium was higher, which allowed suboptimal signals to trigger rapid loss of thymic cellularity.

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Acknowledgements

We thank A. Tarakhovsky (Rockefeller University) for Dicerfl mice; N. Manley (University of Georgia) for Foxn1Cre mice; A. Farr (University of Washington) for hybridomas; S. Schonefeldt for mouse colony support and D. Anz for discussions. Supported by the VIB and Fonds Wetenschappelijk Onderzoek (A.L.), Methusalem financing (KULeuven and Flemish government), European Research Council (B.D.S.), Agentschap voor Innovtie door Wetenschap en Technologie (W.P.), the Australian National Health and Medical Research Council (D.H.D.G.), the European Union consortium “Tolerage” and the Deutsches Krebsforschungszentrum (B.K.).

Author information

Author notes

    • Aikaterini S Papadopoulou
    •  & James Dooley

    These authors contributed equally to this work.

Affiliations

  1. VIB, Leuven, Belgium.

    • Aikaterini S Papadopoulou
    • , James Dooley
    • , Wim Pierson
    • , Bart De Strooper
    •  & Adrian Liston
  2. Center for Human Genetics, University of Leuven, Leuven, Belgium.

    • Aikaterini S Papadopoulou
    •  & Bart De Strooper
  3. Autoimmune Genetics Laboratory, University of Leuven, Leuven, Belgium.

    • James Dooley
    • , Wim Pierson
    •  & Adrian Liston
  4. Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Cambridge, UK.

    • Michelle A Linterman
  5. Developmental Immunology, German Cancer Research Center, Heidelberg, Germany.

    • Olga Ucar
    •  & Bruno Kyewski
  6. Pediatric Immunology, University of Basel, Basel, Switzerland.

    • Saulius Zuklys
    •  & Georg A Hollander
  7. Laboratory of Immunobiology, Rega Institute, University of Leuven, Leuven, Belgium.

    • Patrick Matthys
  8. Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.

    • Daniel H D Gray

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Contributions

A.S.P., J.D., M.A.L., W.P. and O.U. did the experiments; B.K., S.Z., G.A.H. and D.H.D.G. shared data for study design; J.D., P.M., B.D.S. and A.L. designed the study; J.D. and A.L. wrote the manuscript; and all authors read and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to James Dooley or Adrian Liston.

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DOI

https://doi.org/10.1038/ni.2193

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