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The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance

Nature Immunology volume 16, pages 737–745 (2015)Cite this article

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Abstract

Aire is a transcriptional regulator that induces the promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for the induction of immunological self-tolerance. Studies have offered molecular insights into how Aire operates, but more comprehensive understanding of this process still remains elusive. Here we found abundant expression of the protein deacetylase Sirtuin-1 (Sirt1) in mature Aire+ mTECs, wherein it was required for the expression of Aire-dependent TRA-encoding genes and the subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and identifies a unique function for Sirt1 in preventing organ-specific autoimmunity.

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Figure 1: mTECs are the main Sirt1-expressing cells in the immune system.
Figure 2: Sirt1 expression correlates with Aire expression but is Aire independent.
Figure 3: Sirt1 is essential for Aire-driven expression of TRA-encoding genes in vivo.
Figure 4: Sirt1 physically associates with Aire and induces its deacetylation.
Figure 5: Deacetylation of Aire is required for its transcriptional ability.
Figure 6: Sirt1 deficiency resembles Aire-linked organ-specific autoimmunity.

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Acknowledgements

We thank D. Graf (University of Zurich) for B6.Foxn1-Cre mice (with the consent of N. Manley (University of Georgia)); D. Mathis and C. Benoist (Harvard Medical School) for Aire−/− (NOD) mice; M. Anderson (University of California at San Francisco) for Aire-GFP mice; M. Oren (Weizmann Institute) for plasmid pCMV-P300; and N. Or Geva, Z. Porat, G. Hecht, Y. Peleg and O. Brenner for experimental expertise and help. Supported by the Minerva Stiftung (711423), the Israel Science Foundation (1825/10 and 722/14) and the Sy Syms Foundation (J.A.) and the Agence Nationale de Recherche (2011-CHEX-001-R12004KK to M.Gi.).

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Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Anna Chuprin, Ayelet Avin, Yael Goldfarb, Yonatan Herzig, Ben Levi, Adi Jacob, Asaf Sela, Shir Katz & Jakub Abramson

  2. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Moran Grossman & Irit Sagi

  3. Department of Immunology, Institut Cochin, INSERM U1016, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Clotilde Guyon & Matthieu Giraud

  4. The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel

    Moran Rathaus & Haim Y Cohen

  5. Ottawa Hospital Research Institute, Ottawa, Canada

    Michael W McBurney

  6. Department of Clinical Science, University of Bergen, Bergen, Norway

    Eystein S Husebye

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  1. Anna Chuprin
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Contributions

A.C. and J.A. designed the study and wrote the manuscript; A.C. performed most of the experimental work; A.A. performed experiments related to proximity ligation assays. Sirt1 deacetylation, fluorescence microscopy, analysis of serum autoantibodies by slot-blot and enzyme-linked immunosorbent assay; and Y.G., Y.H., B.L., A.J., A.S., S.K., M.Gr., C.G., M.R., H.Y.C., I.S., M.Gi., M.W.M., E.S.H. and J.A. helped in performing, analyzing and/or designing some of the experiments.

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Correspondence to Jakub Abramson.

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The authors declare no competing financial interests.

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Chuprin, A., Avin, A., Goldfarb, Y. et al. The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. Nat Immunol 16, 737–745 (2015). https://doi.org/10.1038/ni.3194

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