Abstract
The thymoproteasome subunit β5t 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 β5t, we showed that aberrant expression of self-peptides generated by β5t affects CD8+ T cell homeostasis, including thymic selection and maintenance of the peripheral naive pool of CD8+ T cells. In mice in which β5t was expressed both in cortical and medullary TECs, the abundance of CD8+ lineage thymocytes was reduced, and extra-thymic expression of β5t caused accumulation of CD8+ T cells with the memory or exhausted phenotype and induced autoreactive T cell responses. We found that thymoproteasomes are essential for positive selection but that the subsequent change in peptide repertoire in the medulla is also crucial for thymic selection and that β5t-derived peptide must be confined to the thymus to avoid autoimmunity in peripheral tissues.