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Sci Immunol. 2017 Jun 2;2(12). pii: eaan5165. doi: 10.1126/sciimmunol.aan5165. Epub 2017 Jun 2.

Human thymoproteasome variations influence CD8 T cell selection.

Author information

1
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
2
Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
3
Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labour and Welfare, Tokyo, Japan.
4
Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
5
Section of Animal Models, Department of Infectious Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
6
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
7
Department of Immunology and Pathology, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan.
8
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
9
Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
10
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan. takayana@m.u-tokyo.ac.jp.

Abstract

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.

PMID:
28783658
DOI:
10.1126/sciimmunol.aan5165

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