A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production
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
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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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 3

G49S variation in mice diminishes β5t expression in cTECs.

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G49S variation in mice diminishes β5t expression in cTECs. (A) H&E s...
(A) H&E staining of thymic sections from indicated mice at 5 weeks old. Representative data from 3 independent experiments are shown. Scale bars: 1 mm. (B) Flow cytometric analysis of enzyme-digested thymic cells isolated from 2-week-old mice of indicated genotypes. Dot plots show CD326 (EpCAM) and CD45 expression in total thymic cells (left), and UEA-1 reactivity and CD249 expression in propidium iodide– (PI–) CD45–CD326+ viable thymic epithelial cells (middle). Graphs show cell number (means ± SEM, n = 4) of PI–CD45–CD326+UEA1–CD249+ cTECs and PI–CD45–CD326+UEA1+CD249– mTECs. (C) Immunofluorescence analysis of β5t (green), Aire (red), and UEA-1 binding molecules (blue) in thymic sections from 5-week-old mice of indicated genotypes. Representative data from 3 independent experiments are shown. Scale bars: 75 μm. (D–F) Histograms show the expression of β5t (D), MHC class I (E), and MHC class II (F) in cTECs and mTECs of WT (black lines), heterozygous (blue lines), and homozygous (red lines) knock-in mice at 2 weeks old. Graphs show relative fluorescence intensity (RFI, n = 3) of β5t (D), MHC class I (E), and MHC class II (F) expression normalized to the mean fluorescence intensity measured in WT cells. *P < 0.05, **P < 0.01 by one-way ANOVA with Tukey’s correction.