Proteasome alteration between epithelial and hematopoietic cells facilitates positive selection of CD8 T cells

The thymoproteasome, a proteolytic complex uniquely expressed in cortical thymic epithelial cells (cTECs), governs the positive selection of CD8 T cells. It was hypothesized that the thymoproteasome promotes CD8 T cell development by forging a sequential switch between cTECs and medullary antigen-presenting cells (APCs), in which stepwise difference in MHC-I-associated peptides by cTECs and medullary APCs would spare positively selected thymocytes from subsequent negative selection. In this study, we engineered mice ectopically expressing thymoproteasomes in various APCs including medullary TECs (mTECs), eliminating the proposed proteasome switch. Surprisingly, we found that the proteasome switch between cTECs and mTECs was dispensable for thymoproteasome-dependent CD8 T cell development. Instead, we found that ectopic thymoproteasomes in hematopoietic cells impaired CD8 T cell development by hindering cortical positive selection.Our findings reveal that proteasome difference between cTECs and hematopoietic cells facilitates thymoproteasome-dependent positive selection in the thymic cortex.