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

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

doi:10.1172/jci.insight.93664

Cited by 7 publications

(8 citation statements)

References 34 publications

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“…Mice deficient in β5t have reduced positive selection of CD8 + thymocytes (20). cTEC restricted expression of β5t is also seen within human TECs, interestingly however analysis of humans carrying mutations within PSMB11 has not revealed any adverse effects (21). Nevertheless, β5t is a defining feature of cTEC that directly underpins at least part of their functional specialization for positive selection.…”

Section: Lineage Specific Thymic Epithelial Cells Ctec and Ctec Hetermentioning

confidence: 99%

Generation and Regeneration of Thymic Epithelial Cells

2020

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The thymus is unique in its ability to support the maturation of phenotypically and functionally distinct T cell sub-lineages. Through its combined production of MHC-restricted conventional CD4 + and CD8 + , and Foxp3 + regulatory T cells, as well as non-conventional CD1d-restricted iNKT cells and invariant γδT cells, the thymus represents an important orchestrator of immune system development and control. It is now clear that thymus function is largely determined by the availability of stromal microenvironments. These specialized areas emerge during thymus organogenesis and are maintained throughout life. They are formed from both epithelial and mesenchymal components, and collectively they support a stepwise program of thymocyte development. Of these stromal cells, cortical, and medullary thymic epithelial cells represent functional components of thymic microenvironments in both the cortex and medulla. Importantly, a key feature of thymus function is that levels of T cell production are not constant throughout life. Here, multiple physiological factors including aging, stress and pregnancy can have either short-or long-term detrimental impact on rates of thymus function. Here, we summarize our current understanding of the development and function of thymic epithelial cells, and relate this to strategies to protect and/or restore thymic epithelial cell function for therapeutic benefit.

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Section: Lineage Specific Thymic Epithelial Cells Ctec and Ctec Hetermentioning

confidence: 99%

Generation and Regeneration of Thymic Epithelial Cells

2020

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“…In addition, it has been shown that a single nucleotide polymorphism that changes the 49 th amino acid from glycine to serine (G49S) in the β5t protein is associated with Sjögren’s syndrome, an autoimmune disease that affects exocrine glands, specifically the lacrimal glands and the salivary glands ( 38 ). On the other hand, another study reported that the G49S variation had little association with severe human diseases, including cancer, hepatitis, and tuberculosis ( 39 ). The G49S variation impaired the post-translational processing of β5t protein in both mouse and human cells, whereas the homozygous G49S variation in mice reduced thymoproteasome expression in cTECs and decreased CD8 + T cell production in the thymus ( 39 ).…”

Section: Human Disease and Genetic Variations In Immunoproteasomes And Thymoproteasomesmentioning

confidence: 99%

The Role of Proteasomes in the Thymus

2021

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The thymus provides a microenvironment that supports the generation and selection of T cells. Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) are essential components of the thymic microenvironment and present MHC-associated self-antigens to developing thymocytes for the generation of immunocompetent and self-tolerant T cells. Proteasomes are multicomponent protease complexes that degrade ubiquitinated proteins and produce peptides that are destined to be associated with MHC class I molecules. cTECs specifically express thymoproteasomes that are essential for optimal positive selection of CD8+ T cells, whereas mTECs, which contribute to the establishment of self-tolerance in T cells, express immunoproteasomes. Immunoproteasomes are also detectable in dendritic cells and developing thymocytes, additionally contributing to T cell development in the thymus. In this review, we summarize the functions of proteasomes expressed in the thymus, focusing on recent findings pertaining to the functions of the thymoproteasomes and the immunoproteasomes.

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“…More than 150 kinds of genomic variations, including single nucleotide polymorphisms in the β5t-coding sequence, have been registered in the National Center for Biotechnology Information (NCBI) public database. Among those variants, the rs34457782 single nucleotide polymorphism that alters the 49th amino acid of the human β5t pro-protein from glycine to serine (G49S) is detected at an appreciable allele frequency in various human populations (66). The 49th amino acid is located at the carboxyl terminus of the pro-peptide that is cleaved to generate catalytically active β5t protein, the amino terminus of which begins at the 50th threonine.…”

Section: Human Genome Variations In β5tmentioning

confidence: 99%

“…The G49S variant in either human β5t or mouse β5t has inefficient processing of the pro-peptide to generate mature β5t protein (66). In mice that are manipulated to carry this variation in the genome, heterozygotes show reduced β5t expression in cTECs and homozygotes further exhibit reduction in the numbers of CD8 + T cells in the thymus and the periphery (66). In cohort studies in humans, however, no severe health problems have been noticed in many heterozygous and a small number of homozygous human individuals (66).…”

Section: Human Genome Variations In β5tmentioning

confidence: 99%

“…In mice that are manipulated to carry this variation in the genome, heterozygotes show reduced β5t expression in cTECs and homozygotes further exhibit reduction in the numbers of CD8 + T cells in the thymus and the periphery (66). In cohort studies in humans, however, no severe health problems have been noticed in many heterozygous and a small number of homozygous human individuals (66). A study has reported that homozygosity in this variation is associated with an elevated risk of Sjögren's syndrome, an autoimmune disease (67).…”

Section: Human Genome Variations In β5tmentioning

confidence: 99%

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Thymus machinery for T-cell selection

Kondo

Ohigashi

Takahama

2018

International Immunology

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An immunocompetent and self-tolerant pool of naive T cells is formed in the thymus through the process of repertoire selection. T cells that are potentially capable of responding to foreign antigens are positively selected in the thymic cortex and are further selected in the thymic medulla to help prevent self-reactivity. The affinity between T-cell antigen receptors expressed by newly generated T cells and self-peptide-major histocompatibility complexes displayed in the thymic microenvironments plays a key role in determining the fate of developing T cells during thymic selection. Recent advances in our knowledge of the biology of thymic epithelial cells have revealed unique machinery that contributes to positive and negative selection in the thymus. In this article, we summarize recent findings on thymic T-cell selection, focusing on the machinery unique to thymic epithelial cells.

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

Cited by 7 publications

References 34 publications

Generation and Regeneration of Thymic Epithelial Cells

Generation and Regeneration of Thymic Epithelial Cells

The Role of Proteasomes in the Thymus

Thymus machinery for T-cell selection

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