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 autophagyindependent 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 macroautophagydependent 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.

The Ubiquitin-like Modifier FAT10 Is Selectively Expressed in Medullary Thymic Epithelial Cells and Modifies T Cell Selection

“…Additionally, in the absence of FAT10, increased percentages of OT-II CD4SP in the thymus were observed, suggesting a reduced negative selection in these mice. Autophagy in thymic epithelium is an essential process in mediating tolerance of CD4 + cells (36,37). It has been demonstrated that the autophagosomal receptor p62/SQSTM1 becomes covalently mono-FAT10ylated at several lysines and that FAT10 colocalizes with p62 in p62 bodies (19).…”

The Human Immune System Recognizes Neopeptides Derived from Mitochondrial DNA Deletions

“…In the case of the class II pathway, once the mt peptides enter the cytosol, they could be recruited into the endosome pathway by autophagy, a well-established mechanism by which viral Ags enter the MHC class II pathway in infected cells (35)(36)(37). Autophagy is the major mechanism by which thymic epithelial cells present Ags, including soluble mt Ags in the class II pathway for negative selection (38)(39)(40). It would be expected that the immune system would be tolerant to normal mt peptides delivered to the class II molecule by autophagy.…”

L’autophagie et l’homéostasie des lymphocytes T et B

“…Les résultats obtenus avec un modèle murin présentant une déficience conditionnelle en ATG7 dans l'épithélium thymique a conduit les auteurs à conclure que l'autophagie ne participait pas à l'édu-cation thymique. On peut cependant penser que dans ce modèle déficient en ATG7, une activité autophagique résiduelle permettrait l'éducation des LT. L'équipe de Klein a montré peu de temps après, grâce à un nouveau modèle de délétion conditionnelle, que l'autophagie des cellules épithéliales thymiques exprimant AIRE (autoimmune regulator) [19] (➜), participait à la sélection négative via la pré-sentation par le CMH de classe II [20]. Le rôle de l'autophagie du stroma thymique dans l'éduca-tion des LT semble conforté par une étude récente.…”

“…Les cellules épithé-liales thymiques (TEC) présentent un niveau élevé d'autophagie basale si on le compare à celui d'autres tissus. Cette activité autophagique permet la présentation de peptides du soi intracellulaires sur le CMH de classe II et intervient dans l'éducation des LT CD4 + [17,20,21]. Les LT déficients en autophagie depuis le développement thymique maintiennent une quantité de mitochondries importante lors de leur passage de la zone centrale vers la zone périphérique, les sensibilisant à l'apoptose [10,12].…”