Regulation of CD8 ⁺ T Cell Development by Thymus-Specific Proteasomes

TLDR

Proteasomes generate peptides for presentation by MHC class I molecules. The study identifies a novel catalytic subunit, beta5t, expressed exclusively in cortical thymic epithelial cells. Beta5t incorporation into proteasomes replaces beta5 or beta5i and selectively reduces chymotrypsin‑like activity. Beta5t‑deficient mice exhibit impaired CD8⁺ T‑cell development, indicating beta5t is essential for generating the MHC class I‑restricted CD8⁺ T‑cell repertoire during thymic selection.

Abstract

Proteasomes are responsible for generating peptides presented by the class I major histocompatibility complex (MHC) molecules of the immune system. Here, we report the identification of a previously unrecognized catalytic subunit called beta5t. beta5t is expressed exclusively in cortical thymic epithelial cells, which are responsible for the positive selection of developing thymocytes. Although the chymotrypsin-like activity of proteasomes is considered to be important for the production of peptides with high affinities for MHC class I clefts, incorporation of beta5t into proteasomes in place of beta5 or beta5i selectively reduces this activity. We also found that beta5t-deficient mice displayed defective development of CD8(+) T cells in the thymus. Our results suggest a key role for beta5t in generating the MHC class I-restricted CD8(+) T cell repertoire during thymic selection.