Critical role for the immunoproteasome subunit LMP7 in the resistance of mice to<i>Toxoplasma gondii</i>infection

Tu, Liping; Moriya, Chikako; Imai, Takashi; Ishida, Hidekazu; Tetsutani, Kohhei; Duan, Xuefeng; Murata, Shigeo; Tanaka, Keiji; Shimokawa, Chikako; Hisaeda, Hajime; Himeno, Kunisuke

doi:10.1002/eji.200939117

Cited by 14 publications

(21 citation statements)

References 47 publications

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“…Nevertheless, it has recently been shown that LMP7 and to a lesser extent LMP2 are crucial for mice to combat Toxoplasma gondii infection (18). Additionally, the lack of LMP7 protracted and lowered the severity of LCMV-induced meningitis in LMP7-deficient mice (22).…”

Section: Discussionmentioning

confidence: 99%

“…The clearance of bacteria from the liver was not apparent by day 10, by which time bacterial burden in the spleen of wild-type mice had decreased. Infection with the protozoan parasite Toxoplasma gondii revealed an even more prominent phenotype (18). In contrast to wild-type mice, b5i-deficient mice were highly susceptible to infection with T. gondii and showed a reduced number of functional T cells.…”

Section: A Ntigen Recognition By Ctls Occurs Through the Interaction mentioning

confidence: 99%

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The Antiviral Immune Response in Mice Devoid of Immunoproteasome Activity

Basler

Beck

Kirk³

et al. 2011

The Journal of Immunology

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The replacement of the catalytically active proteasome subunits β1, β2, and β5 by the immunoproteasome subunits low molecular mass polypeptide (LMP) 2 (β1i), multicatalytic endopeptidase complex-like–1 (MECL-1) (β2i), and LMP7 (β5i) is required for the production of numerous class I ligands. Hitherto, investigation of the immunoproteasome was confined to the analysis of mice deficient for one or two immunosubunits. In this study, we characterized LMP2−/−/MECL-1−/− double-deficient mice and used the well-defined LMP7-selective inhibitor ONX 0914 in these mice to generate mice lacking the activity of all immunoproteasome subunits. LMP2−/−/MECL-1−/− double-deficient mice had strongly reduced numbers of CD8+ T cells in the spleen. Nevertheless, infection with the lymphocytic choriomeningits virus induced a normal cytotoxic T cell response in these mice, although the T cell response to several class I epitopes was altered. Treatment of LMP2−/−/MECL-1−/− double-deficient mice with the LMP7-selective inhibitor ONX 0914 elicited a strong CTL response in lymphocytic choriomeningitis virus-infected mice. Thereby, the TCD8+ response to nucleoprotein 205–212, which is barely detectable in LMP2−/−/MECL-1−/− double-deficient mice, could be reverted to normal levels by LMP7 inhibition. Additional experiments could demonstrate that the increased CTL response to the nucleoprotein 205–212 in mice lacking functional immunoproteasome is due to an altered class I presentation of this epitope. Taken together, to our knowledge, this is the first study investigating viral infection in mice lacking activity of all three immunoproteasome subunits.

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Section: Discussionmentioning

confidence: 99%

Section: A Ntigen Recognition By Ctls Occurs Through the Interaction mentioning

confidence: 99%

The Antiviral Immune Response in Mice Devoid of Immunoproteasome Activity

Basler

Beck

Kirk³

et al. 2011

The Journal of Immunology

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“…Results of previously published studies have provided evidence for decreased T H1 cytokine production in LMP7/ MECL1 double-null mice in response to influenza antigenic epitopes and T. gondii [7] . To distinguish between effects of LMP7/MECL1 on antigen processing and direct effects on cytokine induction, splenocytes were isolated from LMP7/MECL1 double-null mice as well as wildtype mice and activated with PMA and ionomycin ex vivo.…”

Section: Differential Regulation Of T H1 Cytokines By Lmp7 and Mecl1 mentioning

confidence: 92%

“…The impaired antigen presentation resulted in decreased numbers of interferon (IFN) ␥ -producing CD8+ T cells in response to the influenza epitopes [6] . Another group demonstrated diminished IFN ␥ induction in response to Toxoplasma gondii by CD8+ T cells in LMP7-null mice, despite comparable numbers of activated CD8+ T cells [7] .…”

Section: Introductionmentioning

confidence: 99%

A Critical Role for the Inducible Proteasomal Subunits LMP7 and MECL1 in Cytokine Production by Activated Murine Splenocytes

2012

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Background and Purpose: The proteasome is a multi-subunit complex that proteolytically cleaves proteins. The replacement of the constitutive proteasome subunits β1, β2, and/or β5 with the IFNγ-inducible subunits LMP2, MECL1, and/or LMP7 results in the ‘immunoproteasome’. The inducible subunits change the cleavage specificities of the proteasome, but it is unclear whether they have functions in addition to this. The purpose of the present study was to determine the role of the proteasome in general, as well as LMP7 and MECL1 specifically, with regard to cytokine production by activated primary splenocytes. Methods: A LMP7/MECL1-null mouse was engineered to determine the roles of these subunits in cytokine production. Isolated splenocytes from wild-type and LMP7/MECL1–/– mice were treated with lactacystin and activated with PMA and ionomycin and subsequently cytokine mRNA levels were quantified. Results: The present study demonstrates that LMP7/MECL1 regulates the expression of IFNγ, IL4, IL10, IL2Rβ, GATA3, and t-bet. In contrast, the regulation of IL2, IL13, TNFα, and IL2Rα by the proteasome appears to occur independently of LMP7/MECL1. Conclusions: Collectively, the present study demonstrates that LMP7 and MECL1 regulate cytokine expression, suggesting this system represents a novel mechanism for the regulation of cytokines and cytokine signaling.

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“…In conclusion, subunit β5i evolved to efficiently support antigen presentation by producing epitopes with a broad range of hydrophobic C-terminal amino acids for tight binding to MHC I receptors. Its outstanding role for antigen generation is corroborated by a 50 % reduction in MHC I levels in β5i-deficient mice [116] and their enhanced predisposition to infections [117] . Notably, the deletion of the subunits β1i or β2i does not affect MHC I expression [23,118] .…”

Section: Structural and Functional Differences Between The Three Typementioning

confidence: 99%

Structural and Functional Characterization of the Immunoproteasome

Huber¹

2013

Springer Theses

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Critical role for the immunoproteasome subunit LMP7 in the resistance of mice toToxoplasma gondiiinfection

Cited by 14 publications

References 47 publications

The Antiviral Immune Response in Mice Devoid of Immunoproteasome Activity

The Antiviral Immune Response in Mice Devoid of Immunoproteasome Activity

A Critical Role for the Inducible Proteasomal Subunits LMP7 and MECL1 in Cytokine Production by Activated Murine Splenocytes

Structural and Functional Characterization of the Immunoproteasome

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