Human thymoproteasome variations influence CD8 T cell selection

The proteasome is a multi-subunit protease complex essential for housekeeping protein degradation and the production of the major histocompatibility complex (MHC) class I-bound antigen peptides that are essential for recognition by CD8 T cells. MHC variations dramatically contribute to T cell selection and autoimmunity, but genetic variations of peptide processing machinery including proteasome genes have been poorly explored in this context. In the computational analysis of human proteasome gene variation, we documented that PSMB11 was highly enriched for nucleotide changes that interfere with protein function. This gene encodes β5t, a thymus-specific catalytic subunit that regulates positive selection of CD8 T cells by producing a distinct set of MHC class I-bound peptides. The introduction of PSMB11 variations into the mouse genome by genome-editing revealed that these variations impaired the development of CD8 T cells in vivo. One of the PSMB11 polymorphisms altered the CD8 T cell repertoire in mice and was associated with a higher risk of an autoimmune disease in humans. Our findings suggest that, in addition to the MHC haplotype, proteasome variations influence T cell repertoire selection and may contribute to the difference in individual susceptibility to autoimmunity.