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 4

β5t-G49S variation in mice impairs CD8+ T cell production in thymus.

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β5t-G49S variation in mice impairs CD8+ T cell production in thymus. (A)...
(A) Flow cytometric analysis of thymocytes from 5-week-old mice of indicated genotypes. Shown are dot plots of CD4 and CD8 expression (left), TCRβ expression (middle) in PI– viable cells, and dot plots of CD4 and CD8 expression in PI–TCRβhi cells (right). Graphs show the number (means ± SEM, n = 4) of indicated thymocyte populations. (B) Flow cytometric analysis of thymocytes from 5-week-old mice of indicated genotypes. Shown are dot plots of TCRβ and CD5 expression in CD4+CD8+ thymocytes. Boxes indicate TCRβloCD5lo (DP1), TCRβintermediateCD5hi (DP2), and TCRβhiCD5intermediate (DP3) CD4+CD8+ thymocytes. Graphs show the frequency (means ± SEM, n = 4) of indicated thymocyte populations. (C) Flow cytometric analysis of splenocytes from 5-week-old mice of indicated genotypes. Histograms show TCRβ expression in PI– viable cells, and dot plots show CD4 and CD8 expression in PI–TCRβhi viable T cells. Graphs show the number (means ± SEM, n = 4) of CD4+CD8– TCRβhi T cells and CD4–CD8+ TCRβhi T cells. (D) Flow cytometric analysis of splenocytes from 5-week-old mice of indicated genotypes. Shown are dot plots of CD44 and CD122 expression in CD4–CD8+ TCRβhi and CD4+CD8– TCRβhi T cells. Graphs show the number (means ± SEM, n = 4) of indicated splenocyte populations. Numbers in dot plots and histograms indicate frequency of cells within indicated area. *P < 0.05, **P < 0.01 by one-way ANOVA with Tukey’s correction.