A Human PSMB11 Variant Affects Thymoproteasome Processing and CD8+ T Cell Production

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2017 May 19

PMID 28515360

Citations 4

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

Affiliations

Soon will be listed here.

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.

Citing Articles

At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention.

Tundo G, Sbardella D, Oddone F, Kudriaeva A, Lacal P, Belogurov Jr A Cancers (Basel). 2021; 13(19).

PMID: 34638337 PMC: 8507813. DOI: 10.3390/cancers13194852.

The Role of Proteasomes in the Thymus.

Frantzeskakis M, Takahama Y, Ohigashi I Front Immunol. 2021; 12:646209.

PMID: 33815406 PMC: 8017227. DOI: 10.3389/fimmu.2021.646209.

Generation and Regeneration of Thymic Epithelial Cells.

Alawam A, Anderson G, Lucas B Front Immunol. 2020; 11:858.

PMID: 32457758 PMC: 7221188. DOI: 10.3389/fimmu.2020.00858.

Thymus machinery for T-cell selection.

Kondo K, Ohigashi I, Takahama Y Int Immunol. 2018; 31(3):119-125.

PMID: 30476234 PMC: 6400048. DOI: 10.1093/intimm/dxy081.

References

Hanna S, Etzioni A . MHC class I and II deficiencies. J Allergy Clin Immunol. 2014; 134(2):269-75. DOI: 10.1016/j.jaci.2014.06.001. View

Ran F, Hsu P, Lin C, Gootenberg J, Konermann S, Trevino A . Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell. 2013; 154(6):1380-9. PMC: 3856256. DOI: 10.1016/j.cell.2013.08.021. View

Uechi H, Hamazaki J, Murata S . Characterization of the testis-specific proteasome subunit α4s in mammals. J Biol Chem. 2014; 289(18):12365-74. PMC: 4007433. DOI: 10.1074/jbc.M114.558866. View

Nitta T, Murata S, Sasaki K, Fujii H, Mat Ripen A, Ishimaru N . Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity. 2010; 32(1):29-40. DOI: 10.1016/j.immuni.2009.10.009. View

Hanalioglu D, Ayvaz D, Turul Ozgur T, van der Burg M, Sanal O, Tezcan I . A novel mutation in TAP1 gene leading to MHC class I deficiency: Report of two cases and review of the literature. Clin Immunol. 2017; 178:74-78. DOI: 10.1016/j.clim.2017.01.011. View

Takahama Y, Takada K, Murata S, Tanaka K . β5t-containing thymoproteasome: specific expression in thymic cortical epithelial cells and role in positive selection of CD8+ T cells. Curr Opin Immunol. 2012; 24(1):92-8. DOI: 10.1016/j.coi.2012.01.006. View

Mat Ripen A, Nitta T, Murata S, Tanaka K, Takahama Y . Ontogeny of thymic cortical epithelial cells expressing the thymoproteasome subunit β5t. Eur J Immunol. 2011; 41(5):1278-87. DOI: 10.1002/eji.201041375. View

Hamada D, Takata Y, Osabe D, Nomura K, Shinohara S, Egawa H . Association between single-nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population. Arthritis Rheum. 2005; 52(5):1371-80. DOI: 10.1002/art.21013. View

Terao C, Terada N, Matsuo K, Kawaguchi T, Yoshimura K, Hayashi N . A genome-wide association study of serum levels of prostate-specific antigen in the Japanese population. J Med Genet. 2014; 51(8):530-6. DOI: 10.1136/jmedgenet-2014-102423. View

10.

Saini M, Sinclair C, Marshall D, Tolaini M, Sakaguchi S, Seddon B . Regulation of Zap70 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal. 2010; 3(114):ra23. DOI: 10.1126/scisignal.2000702. View

11.

Hirano Y, Kaneko T, Okamoto K, Bai M, Yashiroda H, Furuyama K . Dissecting beta-ring assembly pathway of the mammalian 20S proteasome. EMBO J. 2008; 27(16):2204-13. PMC: 2519102. DOI: 10.1038/emboj.2008.148. View

12.

Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N . Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009; 41(10):1105-9. DOI: 10.1038/ng.449. View

13.

Sakai K, Miyazaki J . A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem Biophys Res Commun. 1997; 237(2):318-24. DOI: 10.1006/bbrc.1997.7111. View

14.

Kitamura T . New experimental approaches in retrovirus-mediated expression screening. Int J Hematol. 1998; 67(4):351-9. DOI: 10.1016/s0925-5710(98)00025-5. View

15.

Xing Y, Jameson S, Hogquist K . Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection. Proc Natl Acad Sci U S A. 2013; 110(17):6979-84. PMC: 3637736. DOI: 10.1073/pnas.1222244110. View

16.

Araki K, Araki M, Miyazaki J, Vassalli P . Site-specific recombination of a transgene in fertilized eggs by transient expression of Cre recombinase. Proc Natl Acad Sci U S A. 1995; 92(1):160-4. PMC: 42837. DOI: 10.1073/pnas.92.1.160. View

17.

Kimura M, Thomas J, Tai X, Guinter T, Shinzawa M, Etzensperger R . Timing and duration of MHC I positive selection signals are adjusted in the thymus to prevent lineage errors. Nat Immunol. 2016; 17(12):1415-1423. PMC: 6691722. DOI: 10.1038/ni.3560. View

18.

Klein L, Kyewski B, Allen P, Hogquist K . Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol. 2014; 14(6):377-91. PMC: 4757912. DOI: 10.1038/nri3667. View

19.

Yuliwulandari R, Sachrowardi Q, Nakajima H, Kashiwase K, Hirayasu K, Mabuchi A . Association of HLA-A, -B, and -DRB1 with pulmonary tuberculosis in western Javanese Indonesia. Hum Immunol. 2010; 71(7):697-701. DOI: 10.1016/j.humimm.2010.04.005. View

20.

Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y . Regulation of CD8+ T cell development by thymus-specific proteasomes. Science. 2007; 316(5829):1349-53. DOI: 10.1126/science.1141915. View