1. Research Institute of Molecular Pathology, Doktor Bohr Gasse 7, 1030 Vienna, Austria
2. Department of Physiology and Cell Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8613, Japan
3. Institute for Immunology, Ludwig-Maximilians-University, Goethestrasse 31, 80336 Munich, Germany
4. 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.).

Correspondence to: Ludger Klein^1,3 Correspondence and requests for materials should be addressed to L.K. (Email: ludger.klein@med.lmu.de).

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 loading^{2, 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 antigens^{7, 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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