Thymoproteasome Shapes Immunocompetent Repertoire of CD8+ T Cells

Nitta, Takeshi; Murata, Shigeo; Sasaki, Katsuhiro; Fujii, Hideki; Ripen, Adiratna Mat; Ishimaru, Naozumi; Koyasu, Shigeo; Tanaka, Keiji; Takahama, Yousuke

doi:10.1016/j.immuni.2009.10.009

Cited by 176 publications

(210 citation statements)

References 81 publications

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“…The different proteasome species in cTECs and mTECs were proposed to generate differences in the pools of negatively and positively selecting MHC class I ligands needed for efficient T cell selection. Mice with a deletion of the subunit β5t were still able to perform the early selection of T cells but these animals formed a small and immune incompetent repertoire of CD8 + T cells which was reduced in number to 20-30 % and were therefore hypersensitive to influenza virus infections (Nitta et al 2010). The question arises, how do chickens or birds compensate for the lack of immuno-and thymoproteasome and what does this mean to our understanding of the function of these proteasomes in thymic selection.…”

Section: Discussionmentioning

confidence: 99%

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

Erath

Groettrup

2014

Immunogenetics

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The proteasome is the main protein-degrading machine within the cell, producing ligands for MHC class I molecules. It is a cylindrical multicatalytic protease complex, and the catalytic activity is mediated by the three subunits β1, β2, and β5 which possess caspase-, trypsin-, and chymotrypsin-like activities, respectively. By stimulation with interferon (IFN)-γ the replacement of these subunits by β1i, β2i, and β5i is induced leading to formation of immunoproteasomes with altered proteolytic and antigen processing properties. The genes coding for these immunosubunits are restricted to jawed vertebrates but have so far not been found in the genomes of birds, e.g., chicken, turkey, quail, black grouse and zebra finch. However, the chicken genome sequences are not completely assigned; therefore, we investigated the presence of immunoproteasome on protein level. 20S proteasome was purified from the chicken brain, blood, spleen, and bursa of Fabricius, followed by separation via two-dimensional (2D) gel electrophoresis. We analyzed the protein spots derived from the spleen and brain by mass spectrometry and could identify all 14 proteasomal subunits, but there were no differences detectable in the spot patterns. Moreover, we stimulated the chicken spleen cells with phorbol 12-myristate 13-acetate (PMA) and ionomycin aiming at the induction of immunoproteasome, but in spite of the induction of proliferation and IFN-γ, no evidence for immunoproteasome formation in chicken could be obtained. This result was substantiated by the finding that 20S proteasomes isolated from immune and non-immune tissues showed very similar peptidolytic activities. Taken together, our results indicate that chicken lack immunoproteasomes also on protein level.

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Section: Discussionmentioning

confidence: 99%

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

Erath

Groettrup

2014

Immunogenetics

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“…Cortical TECs express a unique type of proteasome called the thymoproteasome, characterized by the presence of the b5t catalytic subunit encoded by the Psmb11 gene (59). Cortical TECs contain ∼85% thymoproteasomes (cataLUs b1ib2ib5t) and 15% immunoproteasomes (b1ib2ib5i) (27,59). Other thymic cell populations that may contribute to positive selection, thymocytes and dendritic cells, express mainly immunoproteasomes and a minor proportion of constitutive proteasomes (b1b2b5) (60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

“…whereas other cells can present only thymoproteasome-independent peptides. Expression of thymoproteasomes by cortical TECs is essential for positive selection of most, although not all, CD8 thymocytes (27). Because of their low chymotrypsin-like activity, thymoproteasomes are predicted to generate peptides that bind MHC I molecules with low affinity and, therefore, yield unstable MHCpeptide complexes (59,63).…”

Section: Discussionmentioning

confidence: 99%

Development and Function of Innate Polyclonal TCRαβ+ CD8+ Thymocytes

Rafei

Hardy

Williams

et al. 2011

The Journal of Immunology

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Innate CD8 T cells are found in mutant mouse models, but whether they are produced in a normal thymus remains controversial. Using the RAG2p-GFP mouse model, we found that ∼10% of TCRαβ+ CD4−CD8+ thymocytes were innate polyclonal T cells (GFP+CD44hi). Relative to conventional T cells, innate CD8 thymocytes displayed increased cell surface amounts of B7-H1, CD2, CD5, CD38, IL-2Rβ, and IL-4Rα and downmodulation of TCRβ. Moreover, they overexpressed several transcripts, including T-bet, Id3, Klf2, and, most of all, Eomes. Innate CD8 thymocytes were positively selected, mainly by nonhematopoietic MHCIa+ cells. They rapidly produced high levels of IFN-γ upon stimulation and readily proliferated in response to IL-2 and IL-4. Furthermore, low numbers of innate CD8 thymocytes were sufficient to help conventional CD8 T cells expand and secrete cytokine following Ag recognition. This helper effect depended on CD44-mediated interactions between innate and conventional CD8 T cells. We concluded that innate TCRαβ+ CD8 T cells represent a sizeable proportion of normal thymocytes whose development and function differ in many ways from those of conventional CD8 T cells.

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“…CD8 + T cells generated in the absence of thymoproteasomes displayed a markedly altered T-cell receptor repertoire that was defective in both allogeneic and antiviral responses. 71 Thus, the thymoproteasome is required to generate optimal cellularity of CD8 + T cells and plays an essential role in the development of the MHC class I-restricted CD8 + T-cell repertoire during thymic positive selection. 72 We previously proposed a chromosomal duplication hypothesis to explain the emergence of IFN-γ-regulated subunits.…”

Section: Thymoproteasomementioning

confidence: 99%

The Proteasome: From Basic Mechanisms to Emerging Roles

Tanaka

2013

Keio J. Med.

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The proteasome is a sophisticated, 2.5-MDa, multisubunit complex that contains a catalytic core particle (CP) and two terminal regulatory particles (RPs); the RPs associate with the termini of the central CP at opposite orientations. The CP consists of four axially stacked heptameric rings (two outer α-rings and two inner β-rings), which are made up of seven structurally related, but not identical, α and β subunits. The CP contains catalytic threonine residues (in β1, β2, and β5 with caspase-like, trypsin-like, and chymotrypsin-like activities, respectively) on the surface of the chamber formed by two abutting β-rings. The RP recognizes polyubiquitylated substrate proteins and unfolds and translocates these proteins to the interior of the CP for degradation. The RP comprises 19 different subunits, which are thought to form two subcomplexes called the lid and the base. One longstanding question is how the complex structure of the proteasome is organized with high fidelity. Recently, we proposed a novel assembly mechanism that is assisted by multiple proteasome-dedicated chaperones. In addition, we discovered two immuno-type proteasomes, the immunoproteasome and the thymoproteasome, whose catalytic subunits are replaced by homologous counterparts. These two isoforms perform specialized functions that help discriminate self from non-self in cell-mediated immunity (i.e., they function as enzymes that process intracellular antigens for cytotoxic T lymphocyte responses and thymic positive selection). Moreover, emerging evidence suggests that the proteasome is crucially involved in the pathophysiology of various intractable diseases that are increasing in today's aging society.

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Thymoproteasome Shapes Immunocompetent Repertoire of CD8+ T Cells

Cited by 176 publications

References 81 publications

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

Development and Function of Innate Polyclonal TCRαβ+ CD8+ Thymocytes

The Proteasome: From Basic Mechanisms to Emerging Roles

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