Allele-Selective Effect of PA28 in MHC Class I Antigen Processing

Yamano, Toshihisa; Sugahara, Hidetoshi; Mizukami, Shusaku; Murata, Shigeo; Chiba, Tomoki; Tanaka, Keiji; Yui, Katsuyuki; Udono, Heiichiro

doi:10.4049/jimmunol.181.3.1655

Cited by 24 publications

(23 citation statements)

References 30 publications

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“…Conversely, a substantial increase of antigenicity was observed in B16F1 KbϪ , while a substantial decrease was seen with the H-2Kb-expressing B16 cells. Similar findings were observed using Pmel-1 TCR-transgenic CD8 T cells specific for the H-2Db-restricted gp100 25 epitope, 20 except that IFN␥ increased the antigenicity of all 3 H-2Kb-loss variants (supplemental Figure 8).…”

Section: Noncognate Mhc-i Levels Reduce the Ability Of Ctl To Recognisupporting

confidence: 79%

“…All of the cell lines were cultured in medium supplemented with 10% fetal bovine serum, as recommended by the providers. Transfected B16 cells were prepared with SuperFect reagent (QIAGEN) using various cDNA plasmids: a dominant-negative IFN␥R1 24 (IFN␥R DN ) construct (W. Lee, University of Pennsylvania, Philadelphia, PA); a short hairpin RNA (shRNA) construct for the immunoproteasome PA28␣ subunit 25 (H. Udono, RIKEN Yokohama Institute, Yokohama, Japan); a construct encoding a single-chain trimer H-2Kb-␤2M-Ova 257 (scKb Ova ) 26 molecule (J. Connolly, Washington University, St. Louis, MO); and a plasmid encoding the heavy chain of H-2Kb (L. Pease, Mayo Clinic, Rochester, MN). After transfection, stable clones were isolated with a combination of drug selection, flow cytometric sorting, and cell cloning at limiting dilutions.…”

Section: Cellsmentioning

confidence: 99%

“…Approximately 2 weeks after the primary immunization, the mice were given an identical booster. For generating Pmel-1 TCR-transgenic CTLs, B6 mice received 1 ϫ 10 6 splenocytes from Pmel-1 mice, and the next day they were vaccinated with Hugp100 25 TriVax. CTLs for all in vitro immunologic assays were obtained from TriVax-immunized mice 6 to 7 days after the second immunization.…”

Section: Immunizationsmentioning

confidence: 99%

“…31 However, there is evidence that processing of the Trp2 180 epitope is not compromised by the immunoproteasome. 25,32 Nevertheless, interference RNA technology with the shRNA plasmid was used to inhibit the expression of the PA28␣ subunit, 25 which is required for the immunoproteasome assembly and function. Although a significant reduction (Ͼ 90%) in the expression of PA28␣ in shPA28␣-transduced B16 was achieved, these cells were not recognized by CTLs when treated with IFN␥ (supplemental Figure 5).…”

Section: Mechanisms Involved In the Inhibitory Effects Of Ifn␥mentioning

confidence: 99%

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Interferon γ limits the effectiveness of melanoma peptide vaccines

Cho

Lee

Celis

2011

Blood

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IntroductionBecause cytotoxic T lymphocytes (CTLs) have the ability to recognize and kill tumor cells, considerable efforts are being devoted to the development of T-cell immunotherapies for cancer. [1][2][3] CTLs express the CD8 coreceptor and recognize antigen on tumor cells as peptide/major histocompatibility class I (MHC-I) complexes. As a consequence of antigen recognition, CD8 CTLs exert antitumor function via the perforin-granzyme cytolytic pathway or through cytokines such as interferon gamma (IFN␥) and tumor necrosis factor alpha (TNF␣), which exhibit cytostatic activity. The MHC-I-binding peptides recognized by tumorreactive CD8 T lymphocytes are usually derived from genes preferentially expressed by transformed cells or from tissuedifferentiation antigens. The identification of MHC-I-binding peptides that serve as tumor-rejection CD8 T-cell epitopes has opened the door to developing synthetic peptide cancer vaccines. 4 The discovery of melanoma T-cell epitopes for humans and mice has led to studies assessing the utility of peptide vaccines for the treatment of established disease states. In many of these studies, promising, but ultimately not outstanding, therapeutic effects were attained, indicating that the use of synthetic peptides alone, with commonly used adjuvants such as incomplete Freund adjuvant, or in combination with cytokines constitute relatively weak and ineffective vaccines. [5][6][7][8] Thus, several groups, including ours, have focused on optimizing peptide vaccines with the use of Toll-like receptor agonists and costimulatory antibodies as immunologic adjuvants. [9][10][11][12][13][14] Our goal was to design a peptide immunization strategy that generates T-cell responses similar to those observed during an acute viral infection, in which 10% to 50% of all CD8 T cells are specific for the pathogen. We recently described a vaccine that we call TriVax (named for its 3 components: synthetic peptide, polyriboinosinic-polyribocytidylic acid [poly-IC], and anti-CD40 antibody), which achieved our stated goal. 15,16 In addition to generating large CD8 T-cell responses to a melanosomal epitope (Trp2 180 ), significant therapeutic effects (60% long-term survival) were observed against 3-day established B16 melanomas. The therapeutic effect of TriVax disappeared when CD8 T cells were depleted with antibodies or in perforin-deficient mice. Conversely, the elimination of CD4 T lymphocytes and natural killer cells had no significant effect. 16 These results indicated that the major effector mechanism of TriVax is mediated by classic CD8 CTLs through perforin-mediated lysis of tumor cells. Nevertheless, the therapeutic effect of TriVax decreased if vaccination was administered in more advanced disease states, even though large numbers of functional CD8 T cells were detected in the tumor-bearing mice, suggesting that immune-suppressive activity at the tumor site was responsible for the tumor's evasion from the T cells. During these studies, we observed that the therapeutic effectiveness of TriVax was...

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Section: Noncognate Mhc-i Levels Reduce the Ability Of Ctl To Recognisupporting

confidence: 79%

Section: Cellsmentioning

confidence: 99%

Section: Immunizationsmentioning

confidence: 99%

Section: Mechanisms Involved In the Inhibitory Effects Of Ifn␥mentioning

confidence: 99%

See 2 more Smart Citations

Interferon γ limits the effectiveness of melanoma peptide vaccines

Cho

Lee

Celis

2011

Blood

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“…The binding of PSME1 and PSME2 to the i20S has recently been shown to increase the capacity of i-proteasomes to selectively degrade oxidized proteins (44) and accelerate the generation of a subset of MHC class I-presented antigenic peptides (9,45,46). In addition, in situ PLA showed that both PSME1 associated proteasomes and i-proteasomes were mainly localized in the cytosol of C2C12 cells.…”

Section: Discussionmentioning

confidence: 95%

Identification of the Immunoproteasome as a Novel Regulator of Skeletal Muscle Differentiation

Cui

Hwang

Gomes

2014

Molecular and Cellular Biology

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While many of the molecular details of myogenesis have been investigated extensively, the function of immunoproteasomes (iproteasomes) in myogenic differentiation remains unknown. We show here that the mRNA of i-proteasome subunits, the protein levels of constitutive and inducible proteasome subunits, and the proteolytic activities of the 20S and 26S proteasomes were significantly upregulated during differentiation of skeletal muscle C2C12 cells. Knockdown of the i-proteasome catalytic subunit PSMB9 by short hairpin RNA (shRNA) decreased the expression of both PSMB9 and PSMB8 without affecting other catalytic subunits of the proteasome. PSMB9 knockdown and the use of i-proteasome-specific inhibitors both decreased 26S proteasome activities and prevented C2C12 differentiation. Inhibition of the i-proteasome also impaired human skeletal myoblast differentiation. Suppression of the i-proteasome increased protein oxidation, and these oxidized proteins were found to be more susceptible to degradation by exogenous i-proteasomes. Downregulation of the i-proteasome also increased proapoptotic proteins, including Bax, as well as cleaved caspase 3, cleaved caspase 9, and cleaved poly(ADP-ribose) polymerase (PARP), suggesting that impaired differentiation is likely to occur because of significantly increased apoptosis. These results demonstrate for the first time that i-proteasomes, independent of constitutive proteasomes, are critical for skeletal muscle differentiation of mouse C2C12 cells.

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PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I‐binding peptides in vivo

Graaf¹,

Helden²,

Textoris-Taube³

et al. 2011

Eur J Immunol

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Summary Proteasomes play a fundamental role in the processing of intracellular antigens into peptides that bind to MHC class I molecules for presentation to CD8 T cells. Three IFNγ-inducible catalytic proteasome (immuno)subunits as well as the IFNγ-inducible proteasome activator PA28 dramatically accelerate the generation of a subset of MHC class I-presented antigenic peptides. To determine whether these IFNγ-inducible proteasome components play a compounded role in antigen processing, we generated mice lacking both PA28 and the immunosubunits β5i/LMP7 and β2i/MECL-1. Analyses of MHC class I cell surface levels ex vivo demonstrated that PA28-deficiency reduced the production of MHC class I-binding peptides both in cells with and without immunosubunits, in the last cells on top of an already diminished production of MHC ligands in the absence of immunoproteasomes. In contrast, the immunosubunits but not PA28 appeared to be of critical importance for the induction of CD8 T cell responses to multiple dominant Influenza and Listeria-derived epitopes. Taken together, our data demonstrate that PA28 and the proteasome immunosubunits use fundamentally different mechanisms to enhance the supply of MHC class I-binding peptides. However, only the immunosubunit-imposed effects on proteolytic epitope processing appear to have substantial effects on the fine-specificity of pathogen-specific CD8 T cell responses.

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Allele-Selective Effect of PA28 in MHC Class I Antigen Processing

Cited by 24 publications

References 30 publications

Interferon γ limits the effectiveness of melanoma peptide vaccines

Interferon γ limits the effectiveness of melanoma peptide vaccines

Identification of the Immunoproteasome as a Novel Regulator of Skeletal Muscle Differentiation

PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I‐binding peptides in vivo

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