Restricted Expression of the Thymoproteasome Is Required for Thymic Selection and Peripheral Homeostasis of CD8+ T Cells

The thymoproteasome subunit beta 5t is specifically expressed in cortical thymic epithelial cells (TECs) and generates unique peptides to support positive selection. In this study, using a mouse model ubiquitously expressing beta 5t, we showed that aberrant expression of self-peptides generated by beta 5t affects CD8(+) T cell homeostasis, including thymic selection and maintenance of the peripheral naive pool of CD8(+) T cells. In mice in which beta 5t was expressed both in cortical and medullary TECs, the abundance of CD8(+) lineage thymocytes was reduced, and extra-thymic expression of beta 5t caused accumulation of CD8(+) T cells with the memory or exhausted phenotype and induced autoreactive T cell responses. We found that thymopro-teasomes are essential for positive selection but that the subsequent change in peptide repertoire in the medulla is also crucial for thymic selection and that beta 5t-derived peptide must be confined to the thymus to avoid autoimmunity in peripheral tissues.