The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection

Izumi Ohigashi; Melina Frantzeskakis; Alison Jacques; Sayumi Fujimori; Aya Ushio; Fusano Yamashita; Naozumi Ishimaru; Da Yin; Margaret Cam; Michael C Kelly; Parirokh Awasthi; Kensuke Takada; Yousuke Takahama

doi:10.1084/jem.20201904

The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection

J Exp Med. 2021 Apr 5;218(4):e20201904. doi: 10.1084/jem.20201904.

Authors

Affiliations

¹ Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima, Tokushima, Japan.
² Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
³ Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
⁴ Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁵ Single Cell Analysis Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁶ Transgenic Mouse Model Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁷ Laboratory of Molecular Medicine, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.

Abstract

The thymoproteasome expressed specifically in thymic cortical epithelium optimizes the generation of CD8+ T cells; however, how the thymoproteasome contributes to CD8+ T cell development is unclear. Here, we show that the thymoproteasome shapes the TCR repertoire directly in cortical thymocytes before migration to the thymic medulla. We further show that the thymoproteasome optimizes CD8+ T cell production independent of the thymic medulla; independent of additional antigen-presenting cells, including medullary thymic epithelial cells and dendritic cells; and independent of apoptosis-mediated negative selection. These results indicate that the thymoproteasome hardwires the TCR repertoire of CD8+ T cells with cortical positive selection independent of negative selection in the thymus.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / immunology
Base Sequence
CD8-Positive T-Lymphocytes / immunology*
Cell Differentiation / immunology
Cells, Cultured
Dendritic Cells / immunology
Epithelial Cells / enzymology*
Epithelial Cells / immunology
Epithelium / enzymology
Epithelium / immunology
High-Throughput Nucleotide Sequencing / methods
Mice
Mice, Inbred C57BL
Mice, Knockout
Proteasome Endopeptidase Complex / metabolism*
Receptors, Antigen, T-Cell, alpha-beta / genetics
Receptors, Antigen, T-Cell, alpha-beta / immunology*
Sequence Analysis, RNA / methods
Thymocytes / immunology
Thymus Gland / enzymology*
Thymus Gland / immunology
VDJ Exons

Substances

Receptors, Antigen, T-Cell, alpha-beta
Proteasome Endopeptidase Complex