title: Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance.
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 polypeptides, 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, 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. In doing so, it contributes to T-cell selection and is essential for the generation of a self-tolerant T-cell repertoire.
authors.affiliation: Research Institute of Molecular Pathology, Doktor Bohr Gasse 7, 1030 Vienna, Austria.
authors.forename: Jelena
authors.initials: J
authors.lastname: Nedjic
authors.forename: Martin
authors.initials: M
authors.lastname: Aichinger
authors.forename: Jan
authors.initials: J
authors.lastname: Emmerich
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002454:Cell Differentiation; D002678:Chimera / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D004848:Epithelium / Q000276:immunology*; D005260:Female; D006649:Histocompatibility Antigens / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology* / Q000637:transplantation
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D006649:Histocompatibility Antigens; D008869:Microtubule-Associated Proteins; D011948:Receptors, Antigen, T-Cell