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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

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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Figure 1: Loss of miRNA in the thymic epithelium results in progressive loss of thymic architecture.
Figure 2: Enhanced apoptosis of the medullary thymic epithelium in the absence of miRNA.
Figure 3: Progressive decay in thymocyte differentiation associated with the presence of epithelial voids in Dicer-deficient mice.
Figure 4: Thymic epithelial defects in the miRNA network result in hypersensitivity to IFN-α and premature thymic involution.
Figure 5: Ifnar1 is a direct target of miR-29a.
Figure 6: Thymic involution and architectural alterations segregate in miR-29a-deficient mice.
Figure 7: Thymic epithelial defects in miR-29a result in PAMP hypersensitivity and inappropriate thymic involution.

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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.).

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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.

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Correspondence to James Dooley or Adrian Liston.

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Papadopoulou, A., Dooley, J., Linterman, M. et al. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor. Nat Immunol 13, 181–187 (2012). https://doi.org/10.1038/ni.2193

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