Macroautophagy, endogenous MHC II loading and T cell selection: the benefits of breaking the rules

Functional and biochemical assays indicate a substantial contribution of intracellularly derived peptides to the MHC class II 'ligandome'. Macroautophagy, a process traditionally known for its role in cellular housekeeping and adaptation to nutrient withdrawal, is an attractive candidate pathway for endogenous MHC class II loading. Work in cell culture systems, including antigen presentation assays, co-localization studies and sequencing of MHC class II bound peptides, demonstrates that substrates of autophagy can be loaded onto MHC class II. Advances in the development of mouse models to monitor or genetically disrupt macroautophagy now provide the basis for elucidating the immunological relevance of autophagy in vivo. Here, we will discuss recent findings suggesting a crucial role of macroautophagy in thymic epithelial cells for the generation of peptide/MHC class II ligands for positive selection and induction of T cell tolerance.