Regulation of Immunoproteasome Subunit Expression In Vivo Following Pathogenic Fungal Infection

Barton, Lance F.; Crúz, Miguel A.; Rangwala, Reshma; Deepe, George S.; Monaco, John J.

doi:10.4049/jimmunol.169.6.3046

Cited by 75 publications

(62 citation statements)

References 60 publications

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“…Although TNF-␣ has been shown to up-regulate ␤1i in human cell lines, either alone or synergistically with IFN-␥ (32,33), no effects on expression of these genes were found in fungal infection of mice (34). Our experiments with cytokine receptor knockout (KO) mice demonstrate that lack of TNF-␣ signaling does not influence the induction of I-proteasome during L. monocytogenes infection.…”

Section: Discussionmentioning

confidence: 67%

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

Strehl

Joeris

Rieger

et al. 2006

The Journal of Immunology

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Microbial infections induce the replacement of constitutive proteasomes by immunoproteasomes (I-proteasomes). I-proteasomes support efficient generation of MHC class I epitopes and influence immunodominance hierarchies of CD8+ T cells. Recently, the function of I-proteasomes in antimicrobial responses was challenged by showing that the lack of I-proteasomes has no effect on induction and function of lymphocytic choriomeningitis virus-specific CD8+ T cells. Here, we show that infection with Listeria monocytogenes rapidly induces I-proteasomes in nonlymphoid tissues, which leads to enhanced generation of protection relevant CD8+ T cell epitopes. I-proteasome-deficient mice (β5i−/− mice) exhibited normal frequencies of L. monocytogenes-specific CD8+ T cells. However, clearance of L. monocytogenes in liver but not spleen was significantly impaired in I-proteasome-deficient mice. In summary, our studies demonstrate that induction of I-proteasomes is required for CD8+ T cell-mediated elimination of L. monocytogenes from nonlymphoid but not lymphoid tissues.

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Section: Discussionmentioning

confidence: 67%

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

Strehl

Joeris

Rieger

et al. 2006

The Journal of Immunology

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“…Hepatic 20S proteasomes have an extraordinarily long half-life of 12 to 15 days, as demonstrated in metabolically labeled rats (66), indicating that the replacement of constitutive proteasomes by immunoproteasomes in MCMV-infected livers occurs surprisingly fast. A strong increase in immunoproteasome formation has also been documented in the livers of mice during viral, bacterial, and fungal infections with LCMV, Listeria monocytogenes, and Histoplasma capsulatum (6,39). This effect was markedly reduced in IFN-␥-deficient mice, indicating that this cytokine is indeed a leading factor driving proteasome replacement in vivo (39).…”

Section: Discussionmentioning

confidence: 78%

A Cytomegalovirus Inhibitor of Gamma Interferon Signaling Controls Immunoproteasome Induction

Khan

Zimmermann

Basler

et al. 2004

J Virol

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Both human and mouse cytomegaloviruses (HCMV and MCMV) avoid peptide presentation through the major histocompatibility complex (MHC) class I pathway to CD8؉ T cells. Within the MHC class I pathway, the vast majority of antigenic peptides are generated by the proteasome system, a multicatalytic protease complex consisting of constitutive subunits, three of which can be replaced by enzymatically active gamma interferon (IFN-␥)-inducible subunits, i.e., LMP2, LMP7, and MECL1, to form the so-called immunoproteasomes. Here, we show that steady-state levels of immunoproteasomes are readily formed in response to MCMV infection in the liver. In contrast, the incorporation of immunoproteasome subunits was prevented in MCMVinfected, as well as HCMV-infected, fibroblasts in vitro. Likewise, the expression of the IFN-␥-inducible proteasome regulator PA28␣␤ was also impaired in MCMV-infected cells. Both MCMV and HCMV did not alter the constitutive-subunit composition of proteasomes in infected cells. Quantitative assessment of LMP2, MECL1, and LMP7 transcripts revealed that the inhibition of immunoproteasome formation occurred at a pretranscriptional level. Remarkably, a targeted deletion of the MCMV gene M27, encoding an inhibitor of STAT2 that disrupts IFN-␥ receptor signaling, largely restored transcription and protein expression of immunoproteasome subunits in infected cells. While CMV block peptide transport and MHC class I assembly by posttranslational strategies, immunoproteasome assembly, and thus the repertoire of proteasomal peptides, is controlled by pretranscriptional mechanisms. We hypothesize that the blockade of immunoproteasome formation has considerable consequences for shaping the CD8 ؉ -T-cell repertoire during the effector phase of the immune response.Human cytomegalovirus (HCMV), a prototype member of the betaherpesvirus subfamily, is an important pathogen and can cause a wide range of disease manifestations. Primary infection in the immunocompetent host is usually asymptomatic, whereas in the immunocompromised host infection or virus reactivation from latency can cause severe and even fatal disease. Mouse cytomegalovirus (MCMV) shows a similar pathobiology and has a collinear genome (47). Studies of humans and of the mouse have revealed that virus-specific CD8 ϩ T lymphocytes represent the dominant effector arm of protective immunity. For immune recognition, the infected cells present virus-derived peptides on their major histocompatibility complex (MHC) class I molecules to CD8 ϩ cytotoxic T lymphocytes. The processing and presentation of viral peptides is therefore the basis for immune recognition of infected cells, and a change in or lack of peptide supply can undermine the efficiency of T-cell recognition and result in immune evasion of the virus. Both HCMV and MCMV avoid peptide presentation by the expression of several viral glycoproteins (gps) controlling distinct checkpoints of the MHC class I presentation pathway. Specifically, the HCMV US6-encoded gp shuts off the translocation of peptides acr...

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“…3A). (39). Western blot analyses revealed that the proteasome isolated from A2K b mice contained indeed the three subunits LMP2, LMP7, and MECL-1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Processing of Tumor-Associated Antigen by the Proteasomes of Dendritic Cells ControlsIn vivoT-Cell Responses

et al. 2006

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Regulation of Immunoproteasome Subunit Expression In Vivo Following Pathogenic Fungal Infection

Cited by 75 publications

References 60 publications

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

A Cytomegalovirus Inhibitor of Gamma Interferon Signaling Controls Immunoproteasome Induction

Processing of Tumor-Associated Antigen by the Proteasomes of Dendritic Cells ControlsIn vivoT-Cell Responses

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