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

• Published in: Science (American Association for the Advancement of Science) 2007-06, Vol.316 (5829), p.1349-1353
• Main Authors: Murata, Shigeo, Sasaki, Katsuhiro, Kishimoto, Toshihiko, Niwa, Shin-ichiro, Hayashi, Hidemi, Takahama, Yousuke, Tanaka, Keiji
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Animals; Autoantigens - immunology; Autoantigens - metabolism; Biological and medical sciences; Biomedical research; Catalysis; Catalytic Domain; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cellular biology; Cellular immunity; Endocrine system; Epithelial cells; Epithelial Cells - enzymology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Humans; Immunology; Ligands; Lymphopoiesis; Molecular Sequence Data; Molecules; Peptides; Peptides - chemistry; Peptides - metabolism; Positive selection; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Rodents; Spleen - cytology; Spleen - immunology; Stem cells; Stromal cells; T lymphocytes; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; Thymocytes; Thymus Gland - cytology; Thymus Gland - enzymology; Thymus Gland - immunology; Tissue, organ and graft immunology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1141915

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 β5t. β5t 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 β5t into proteasomes in place of β5 or β5i selectively reduces this activity. We also found that β5t-deficient mice displayed defective development of CD8⁺ T cells in the thymus. Our results suggest a key role for β5t in generating the MHC class I-restricted CD8⁺ T cell repertoire during thymic selection.