title: Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance.
abstract: Macroautophagy serves cellular housekeeping and metabolic functions through delivery of cytoplasmic constituents for lysosomal degradation. In addition, it may mediate the unconventional presentation of intracellular antigens to CD4(+) T cells; however, the physiological relevance of this endogenous MHC class II loading pathway remains poorly defined. Here, we characterize the role of macroautophagy in thymic epithelial cells (TECs) for negative selection. Direct presentation for clonal deletion of MHC class II-restricted thymocytes required macroautophagy for a mitochondrial version of a neo-antigen, but was autophagy-independent for a membrane-bound form. A model antigen specifically expressed in Aire(+) medullary TECs (mTECs) induced efficient deletion via direct presentation when targeted to autophagosomes, whereas interference with autophagosomal routing of this antigen through exchange of a single amino acid or ablation of an essential autophagy gene abolished direct presentation for negative selection. Furthermore, when this autophagy substrate was expressed by mTECs in high amounts, endogenous presentation and indirect presentation by DCs operated in a redundant manner, whereas macroautophagy-dependent endogenous loading was essential for clonal deletion at limiting antigen doses. Our findings suggest that macroautophagy supports central CD4(+) T cell tolerance through facilitating the direct presentation of endogenous self-antigens by mTECs.
authors: Institute for Immunology, Ludwig-Maximilians-Universität, 80336 Munich, Germany.
authors: Martin
authors: M
authors: Aichinger
authors: Chunyan
authors: C
authors: Wu
authors: Jelena
authors: J
authors: Nedjic
authors: Ludger
authors: L
authors: Klein
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001343:Autophagy / Q000276:immunology*; D030161:Avian Proteins / Q000276:immunology; D002097:C-Reactive Protein / Q000235:genetics / Q000276:immunology; D061167:Central Tolerance; D017637:Clonal Deletion; D010856:Columbidae; D045304:Cytochromes c / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D000096927:AIRE Protein
chemical_list: D030161:Avian Proteins; D002097:C-Reactive Protein; D045304:Cytochromes c; D000949:Histocompatibility Antigens Class II; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000096927:AIRE Protein
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