Figure 1. Thymic epithelial cells use macroautophagy to shuttle intracellular antigens into the MHC II loading pathway. In mTECs, the AIRE protein promotes the ‘promiscuous expression’ of peripheral tissue-antigens. Cytoplasmic self-antigens in mTECs are loaded onto MHC I for CD8 T cell tolerance via the ‘conventional’ MHC I pathway that involves the proteasomal degradation of substrates and the subsequent delivery of peptides into the endoplasmic reticulum. However, these cytoplasmic antigens may also be loaded onto MHC II for CD4 T cell tolerance through an ‘unconventional’ MHC II pathway, whereby subsequent to being engulfed by an autophagosome, these substrates are proteolytically processed by lysosomal proteases prior to reaching MHC II loading compartments.