Aberrant expression of β5t in the periphery induces a self-reactive T-cell response

Abstract The thymoproteasome subunit β5t is specifically expressed in cortical thymic epithelial cells (cTECs) and generates unique peptides to support positive selection. However, in the context of systemic immune homeostasis, it remains unclear why the expression of β5t-containing proteasomes is restricted to the thymus. In this study, using a mouse model ubiquitously expressing β5t (β5i−/−β5t-Tg), we showed that the aberrant peripheral expression of self-peptides generated by β5t affects the peripheral naïve pool of CD8+ T cells. In β5i−/−β5t-Tg mice, the percentage of naïve CD44lowCD122lowwas reduced, and the percentage of memory CD44highCD122high CD8+ T cells was significantly elevated. When naïve CD44lowCD122low CD8+ T cells from EGFP mice, which exhibited the wild type (WT) phenotype and underwent thymic selection by β5t-expressing cTECs, were transferred into β5i−/−β5t-Tg, transferred cells changed their phenotype from CD44lowCD122low to CD44highCD122high. The transferred EGFP+ CD8+ T cells with a CD44highCD122high phenotype showed increased expression of PD-1 and Tim-3, and these alterations were affected by the condition of peripheral antigen-presenting cells in β5i−/−β5t-Tg recipient mice. The transferred CD8+ T cells from WT mice caused chronic inflammation in β5i−/−β5t-Tg recipient mice. These results demonstrate that the aberrant peripheral expression of β5t disrupts the maintenance of a naïve pool of CD8+ T cells and induces autoreactive T-cell responses. The self-peptides generated by β5t are required to confine in the thymus to avoid autoimmunity in the peripheral tissues, and self-peptides mimicking β5t-producing peptides in the periphery may cause the failure of immunological regulation and tolerance.