Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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 181–187 (2012)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Miller, J.F. Immunological function of the thymus. Lancet 2, 748–749 (1961).

    Article  CAS  Google Scholar 

  2. Itoh, M. et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162, 5317–5326 (1999).

    CAS  Google Scholar 

  3. King, C.C. et al. Viral infection of the thymus. J. Virol. 66, 3155–3160 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Anz, D. et al. Activation of melanoma differentiation-associated gene 5 causes rapid involution of the thymus. J. Immunol. 182, 6044–6050 (2009).

    Article  CAS  Google Scholar 

  5. Aronson, M. Hypothesis: involution of the thymus with aging–programmed and beneficial. Thymus 18, 7–13 (1991).

    CAS  PubMed  Google Scholar 

  6. Dowling, M.R. & Hodgkin, P.D. Why does the thymus involute? A selection-based hypothesis. Trends Immunol. 30, 295–300 (2009).

    Article  CAS  Google Scholar 

  7. Fu, Y., Paul, R.D., Wang, Y. & Lopez, D.M. Thymic involution and thymocyte phenotypic alterations induced by murine mammary adenocarcinomas. J. Immunol. 143, 4300–4307 (1989).

    CAS  PubMed  Google Scholar 

  8. Olsen, N.J., Olson, G., Viselli, S.M., Gu, X. & Kovacs, W.J. Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology 142, 1278–1283 (2001).

    Article  CAS  Google Scholar 

  9. Sutherland, J.S. et al. Activation of thymic regeneration in mice and humans following androgen blockade. J. Immunol. 175, 2741–2753 (2005).

    Article  CAS  Google Scholar 

  10. Domínguez-Gerpe, L. & Rey-Mendez, M. Time-course of the murine lymphoid tissue involution during and following stressor exposure. Life Sci. 61, 1019–1027 (1997).

    Article  Google Scholar 

  11. Sasaki, S., Ishida, Y., Nishio, N., Ito, S. & Isobe, K. Thymic involution correlates with severe ulcerative colitis induced by oral administration of dextran sulphate sodium in C57BL/6 mice but not in BALB/c mice. Inflammation 31, 319–328 (2008).

    Article  CAS  Google Scholar 

  12. Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007).

    Article  CAS  Google Scholar 

  13. Martinez-Nunez, R.T., Louafi, F., Friedmann, P.S. & Sanchez-Elsner, T. MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) by down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J. Biol. Chem. 284, 16334–16342 (2009).

    Article  CAS  Google Scholar 

  14. Taganov, K.D., Boldin, M.P., Chang, K.J. & Baltimore, D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. USA 103, 12481–12486 (2006).

    Article  CAS  Google Scholar 

  15. Liu, G. et al. miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proc. Natl. Acad. Sci. USA 106, 15819–15824 (2009).

    Article  CAS  Google Scholar 

  16. Sheedy, F.J. et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat. Immunol. 11, 141–147 (2010).

    Article  CAS  Google Scholar 

  17. Androulidaki, A. et al. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31, 220–231 (2009).

    Article  CAS  Google Scholar 

  18. Liston, A., Linterman, M. & Lu, L.F. MicroRNA in the adaptive immune system, in sickness and in health. J. Clin. Immunol. 30, 339–346 (2010).

    Article  CAS  Google Scholar 

  19. Hou, J. et al. MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J. Immunol. 183, 2150–2158 (2009).

    Article  CAS  Google Scholar 

  20. Liston, A. et al. Lack of Foxp3 function and expression in the thymic epithelium. J. Exp. Med. 204, 475–480 (2007).

    Article  CAS  Google Scholar 

  21. Yi, R. et al. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat. Genet. 38, 356–362 (2006).

    Article  CAS  Google Scholar 

  22. Betel, D., Wilson, M., Gabow, A., Marks, D.S. & Sander, C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 36, D149–D153 (2008).

    Article  CAS  Google Scholar 

  23. Hwang, H.W., Wentzel, E.A. & Mendell, J.T. A hexanucleotide element directs microRNA nuclear import. Science 315, 97–100 (2007).

    Article  CAS  Google Scholar 

  24. Sheehan, K.C.F. et al. Blocking monoclonal antibodies specific for mouse IFN-α/β receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. J. Interferon Cytokine Res. 26, 804–819 (2006).

    Article  CAS  Google Scholar 

  25. Muljo, S.A. et al. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005).

    Article  CAS  Google Scholar 

  26. Cobb, B.S. et al. T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer. J. Exp. Med. 201, 1367–1373 (2005).

    Article  CAS  Google Scholar 

  27. Koralov, S.B. et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 132, 860–874 (2008).

    Article  CAS  Google Scholar 

  28. Kuipers, H., Schnorfeil, F.M., Fehling, H.J., Bartels, H. & Brocker, T. Dicer-dependent microRNAs control maturation, function, and maintenance of Langerhans cells in vivo. J. Immunol. 185, 400–409 (2010).

    Article  CAS  Google Scholar 

  29. Liston, A., Lu, L.F., O'Carroll, D., Tarakhovsky, A. & Rudensky, A.Y. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J. Exp. Med. 205, 1993–2004 (2008).

    Article  CAS  Google Scholar 

  30. Rodewald, H.R., Paul, S., Haller, C., Bluethmann, H. & Blum, C. Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763–768 (2001).

    Article  CAS  Google Scholar 

  31. Sato, T. et al. Surface molecules essential for positive selection are retained but interfered in thymic epithelial cells after monolayer culture. Cell. Immunol. 211, 71–79 (2001).

    Article  CAS  Google Scholar 

  32. Flomerfelt, F.A., Kim, M.G. & Schwartz, R.H. Spatial, a gene expressed in thymic stromal cells, depends on three-dimensional thymus organization for its expression. Genes Immun. 1, 391–401 (2000).

    Article  CAS  Google Scholar 

  33. Fukagawa, T. et al. Dicer is essential for formation of the heterochromatin structure in vertebrate cells. Nat. Cell Biol. 6, 784–791 (2004).

    Article  CAS  Google Scholar 

  34. Anderson, G., Pongracz, J., Parnell, S. & Jenkinson, E.J. Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signaling. Eur. J. Immunol. 31, 3349–3354 (2001).

    Article  CAS  Google Scholar 

  35. Wilson, A., MacDonald, H.R. & Radtke, F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J. Exp. Med. 194, 1003–1012 (2001).

    Article  CAS  Google Scholar 

  36. Bix, M. & Raulet, D. Inefficient positive selection of T cells directed by haematopoietic cells. Nature 359, 330–333 (1992).

    Article  CAS  Google Scholar 

  37. Lu, L.F. & Liston, A. MicroRNA in the immune system, microRNA as an immune system. Immunology 127, 291–298 (2009).

    Article  CAS  Google Scholar 

  38. Fedeli, M. et al. Dicer-dependent microRNA pathway controls invariant NKT cell development. J. Immunol. 183, 2506–2512 (2009).

    Article  CAS  Google Scholar 

  39. Lynn, F.C. et al. MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes 56, 2938–2945 (2007).

    Article  CAS  Google Scholar 

  40. Wiesen, J.L. & Tomasi, T.B. Dicer is regulated by cellular stresses and interferons. Mol. Immunol. 46, 1222–1228 (2009).

    Article  CAS  Google Scholar 

  41. Gordon, J. et al. Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus. BMC Dev. Biol. 7, 69 (2007).

    Article  Google Scholar 

  42. Geboes, L. et al. Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum. 60, 390–395 (2009).

    Article  CAS  Google Scholar 

  43. Kelchtermans, H. et al. Defective CD4+CD25+ regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-gamma. Arthritis Res. Ther. 7, R402–R415 (2005).

    Article  CAS  Google Scholar 

  44. Dooley, J., Erickson, M. & Farr, A.G. Alterations of the medullary epithelial compartment in the Aire-deficient thymus: implications for programs of thymic epithelial differentiation. J. Immunol. 181, 5225–5232 (2008).

    Article  CAS  Google Scholar 

  45. Silahtaroglu, A.N. et al. Detection of microRNAs in frozen tissue sections by fluorescence in situ hybridization using locked nucleic acid probes and tyramide signal amplification. Nat. Protoc. 2, 2520–2528 (2007).

    Article  CAS  Google Scholar 

  46. Dooley, J., Erickson, M. & Farr, A.G. An organized medullary epithelial structure in the normal thymus expresses molecules of respiratory epithelium and resembles the epithelial thymic rudiment of nude mice. J. Immunol. 175, 4331–4337 (2005).

    Article  CAS  Google Scholar 

  47. Livak, K.J. & Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT Method. Methods 25, 402–408 (2001).

    Article  CAS  Google Scholar 

Download references

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

  1. Aikaterini S Papadopoulou and James Dooley: These authors contributed equally to this work.

Authors and 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

Authors
  1. Aikaterini S Papadopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James Dooley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michelle A Linterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wim Pierson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olga Ucar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruno Kyewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Saulius Zuklys
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Georg A Hollander
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Patrick Matthys
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniel H D Gray
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bart De Strooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Adrian Liston
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to James Dooley or Adrian Liston.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–16 and Tables 1–4 (PDF 1494 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing