A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production
Izumi Ohigashi, … , Shigeo Murata, Yousuke Takahama
Izumi Ohigashi, … , Shigeo Murata, Yousuke Takahama
Published May 18, 2017
Citation Information: JCI Insight. 2017;2(10):e93664. https://doi.org/10.1172/jci.insight.93664.
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Research Article Genetics Immunology

A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production

Abstract

The Psmb11-encoded β5t subunit of the thymoproteasome, which is specifically expressed in cortical thymic epithelial cells (cTECs), is essential for the optimal positive selection of functionally competent CD8+ T cells in mice. Here, we report that a human genomic PSMB11 variation, which is detectable at an appreciable allele frequency in human populations, alters the β5t amino acid sequence that affects the processing of catalytically active β5t proteins. The introduction of this variation in the mouse genome revealed that the heterozygotes showed reduced β5t expression in cTECs and the homozygotes further exhibited reduction in the cellularity of CD8+ T cells. No severe health problems were noticed in many heterozygous and 5 homozygous human individuals. Long-term analysis of health status, particularly in the homozygotes, is expected to improve our understanding of the role of the thymoproteasome-dependent positive selection of CD8+ T cells in humans.

Authors

Izumi Ohigashi, Yuki Ohte, Kazuya Setoh, Hiroshi Nakase, Akiko Maekawa, Hiroshi Kiyonari, Yoko Hamazaki, Miho Sekai, Tetsuo Sudo, Yasuharu Tabara, Hiromi Sawai, Yosuke Omae, Rika Yuliwulandari, Yasuhito Tanaka, Masashi Mizokami, Hiroshi Inoue, Masanori Kasahara, Nagahiro Minato, Katsushi Tokunaga, Keiji Tanaka, Fumihiko Matsuda, Shigeo Murata, Yousuke Takahama

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Figure 5

Less severe reduction in β5t expression and CD8+ T cells in β5t-G49S–knock-in mice than β5t-deficient mice.

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Less severe reduction in β5t expression and CD8+ T cells in β5t-G49S–kno...
(A) Relative fluorescence intensity (RFI, means ± SEM, n = 3) of β5t expression in cTECs from 2-week-old β5t-G49S homozygous–knock-in mice (homo) and β5t-deficient mice (KO), normalized to the mean fluorescence intensity measured in WT cTECs. (B and C) Frequency (means ± SEM, n = 3) of CD4–CD8+ cells in TCRβhi cells of thymocytes (B) and splenocytes (C) in 6-week-old WT mice, β5t-G49S homozygous–knock-in mice (homo), and β5t-deficient mice (KO). *P < 0.05, **P < 0.01, ***P < 0.001 by one-way ANOVA with Tukey’s correction.