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.

  • Letter
  • Published:

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

Nature volume 455, pages 396–400 (2008)Cite this article

Abstract

Recognition of self-antigen-derived epitopes presented by major histocompatibility complex class II (MHC II) molecules on thymic epithelial cells (TECs) is critical for the generation of a functional and self-tolerant CD4 T-cell repertoire. Whereas haematopoietic antigen-presenting cells generate MHC-II–peptide complexes predominantly through the processing of endocytosed polypeptides1, it remains unknown if and how TECs use unconventional pathways of antigen presentation. Here we address the role of macroautophagy, a process that has recently been shown to allow for endogenous MHC II loading2,3,4,5,6, in T-cell repertoire selection in the mouse thymus. In contrast to most other tissues, TECs had a high constitutive level of autophagy. Genetic interference with autophagy specifically in TECs led to altered selection of certain MHC-II-restricted T-cell specificities and resulted in severe colitis and multi-organ inflammation. Our findings indicate that autophagy focuses the MHC-II–peptide repertoire of TECs on their intracellular milieu, which notably comprises a wide array of otherwise strictly ‘tissue-specific’ self antigens7,8. In doing so, it contributes to T-cell selection and is essential for the generation of a self-tolerant T-cell repertoire.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Constitutive autophagy in TECs.
Figure 2: Epithelial differentiation in the absence of Atg5.
Figure 3: Atg5 deficiency modulates selection of MHC-II-restricted TCR specificities and the abundance of a specific MHCp complex.
Figure 4: Atg5 deficiency in thymic epithelium causes colitis and multiorgan lymphoid infiltration.

Similar content being viewed by others

References

  1. Trombetta, E. S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo . Annu. Rev. Immunol. 23, 975–1028 (2005)

    Article  CAS  Google Scholar 

  2. Schmid, D., Pypaert, M. & Munz, C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26, 79–92 (2007)

    Article  CAS  Google Scholar 

  3. Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005)

    Article  ADS  CAS  Google Scholar 

  4. Nimmerjahn, F. et al. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur. J. Immunol. 33, 1250–1259 (2003)

    Article  CAS  Google Scholar 

  5. Dorfel, D. et al. Processing and presentation of HLA class I and II epitopes by dendritic cells after transfection with in vitro-transcribed MUC1 RNA. Blood 105, 3199–3205 (2005)

    Article  Google Scholar 

  6. Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl Acad. Sci. USA 102, 7922–7927 (2005)

    Article  ADS  CAS  Google Scholar 

  7. Kyewski, B. & Klein, L. A central role for central tolerance. Annu. Rev. Immunol. 24, 571–606 (2006)

    Article  CAS  Google Scholar 

  8. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science 298, 1395–1401 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003)

    Article  CAS  Google Scholar 

  10. Aschenbrenner, K. et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nature Immunol. 8, 351–358 (2007)

    Article  CAS  Google Scholar 

  11. Gallegos, A. M. & Bevan, M. J. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049 (2004)

    Article  CAS  Google Scholar 

  12. Klein, L., Roettinger, B. & Kyewski, B. Sampling of complementing self-antigen pools by thymic stromal cells maximizes the scope of central T cell tolerance. Eur. J. Immunol. 31, 2476–2486 (2001)

    Article  CAS  Google Scholar 

  13. Tewari, M. K., Sinnathamby, G., Rajagopal, D. & Eisenlohr, L. C. A cytosolic pathway for MHC class II-restricted antigen processing that is proteasome and TAP dependent. Nature Immunol. 6, 287–294 (2005)

    Article  CAS  Google Scholar 

  14. Zhou, D. et al. Lamp-2a facilitates MHC class II presentation of cytoplasmic antigens. Immunity 22, 571–581 (2005)

    Article  CAS  Google Scholar 

  15. Levine, B. & Klionsky, D. J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463–477 (2004)

    Article  CAS  Google Scholar 

  16. Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004)

    Article  CAS  Google Scholar 

  17. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004)

    Article  ADS  CAS  Google Scholar 

  18. Mizushima, N. et al. Dissection of autophagosome formation using Atg5-deficient mouse embryonic stem cells. J. Cell Biol. 152, 657–668 (2001)

    Article  CAS  Google Scholar 

  19. Rossi, S. W. et al. RANK signals from CD4+3- inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204, 1267–1272 (2007)

    Article  CAS  Google Scholar 

  20. Gray, D., Abramson, J., Benoist, C. & Mathis, D. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J. Exp. Med. 204, 2521–2528 (2007)

    Article  CAS  Google Scholar 

  21. Derbinski, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33–45 (2005)

    Article  CAS  Google Scholar 

  22. Huang, J. & Klionsky, D. J. Autophagy and human disease. Cell Cycle 6, 1837–1849 (2007)

    Article  CAS  Google Scholar 

  23. Tourne, S. et al. Selection of a broad repertoire of CD4+ T cells in H-2Ma0/0 mice. Immunity 7, 187–195 (1997)

    Article  CAS  Google Scholar 

  24. Ignatowicz, L., Kappler, J. & Marrack, P. The repertoire of T cells shaped by a single MHC/peptide ligand. Cell 84, 521–529 (1996)

    Article  CAS  Google Scholar 

  25. Nakagawa, T. et al. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280, 450–453 (1998)

    Article  ADS  CAS  Google Scholar 

  26. Murata, S. et al. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316, 1349–1353 (2007)

    Article  ADS  CAS  Google Scholar 

  27. Murphy, D. B. et al. A novel MHC class II epitope expressed in thymic medulla but not cortex. Nature 338, 765–768 (1989)

    Article  ADS  CAS  Google Scholar 

  28. Pua, H. H., Dzhagalov, I., Chuck, M., Mizushima, N. & He, Y. W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204, 25–31 (2007)

    Article  CAS  Google Scholar 

  29. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 . Nature Genet. 39, 207–211 (2007)

    Article  CAS  Google Scholar 

  30. Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007)

    Article  CAS  Google Scholar 

  31. Klein, L., Klein, T., Ruther, U. & Kyewski, B. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med. 188, 5–16 (1998)

    Article  CAS  Google Scholar 

  32. Kirberg, J. et al. Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor. J. Exp. Med. 180, 25–34 (1994)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge support from the Austrian National Science Fund (Sonderforschungsbereich F023 and grant Z58-B01 ‘Wittgenstein Prize Meinrad Busslinger’; to J.N. and L.K.) and the European Union (FP6 Integrated Project ‘Eurothymaide’; Contract LSHB-CT-2003-503410; to M.A., J.E. and L.K.). Research at the Research Institute of Molecular Pathology is funded by Boehringer Ingelheim. We thank C. Spona for technical assistance and M. Busslinger, M. S. Anderson, B. Kyewski and J. Derbinski for comments on the manuscript. We also thank H. Ploegh for discussions in the earliest phase of this project.

Author Contributions J.N. was involved in all experiments (assisted by J.E., M.A. and L.K.). M.A. carried out the analysis of TRA expression. J.N., N.M. and L.K. designed experimental strategies. J.N. and L.K. wrote the manuscript. All authors discussed and commented on the contents of this manuscript.

Author information

Author notes

  1. Jelena Nedjic, Martin Aichinger & Jan Emmerich

    Present address: Present addresses: Institute for Immunology, Ludwig-Maximilians-University, Goethestrasse 31, 80336 Munich, Germany (J.N., M.A.); Schering-Plough BioPharma (formerly DNAX, Inc.), 901 California Avenue, Palo Alto, California 94304, USA (J.E.).,

Authors and Affiliations

  1. Research Institute of Molecular Pathology, Doktor Bohr Gasse 7, 1030 Vienna, Austria ,

    Jelena Nedjic, Martin Aichinger, Jan Emmerich & Ludger Klein

  2. Department of Physiology and Cell Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8613, Japan,

    Noboru Mizushima

  3. Institute for Immunology, Ludwig-Maximilians-University, Goethestrasse 31, 80336 Munich, Germany ,

    Ludger Klein

Authors
  1. Jelena Nedjic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Aichinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan Emmerich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Noboru Mizushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ludger Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ludger Klein.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1 - 11 and Supplementary Tables 1 - 2 with Legends. (PDF 798 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nedjic, J., Aichinger, M., Emmerich, J. et al. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455, 396–400 (2008). https://doi.org/10.1038/nature07208

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07208

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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