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