The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses

Schwarz, Katrin; Giuli, Rita de; Schmidtke, Gunter; Kostka, Susanne; Broek, Maries van den; Kim, Kyung Bo; Crews, Craig M.; Kraft, Regine; Groettrup, Marcus

doi:10.4049/jimmunol.164.12.6147

Cited by 95 publications

(86 citation statements)

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“…The lacZ-based color reaction was performed and measured, as detailed elsewhere (27). In case of vaccinia-infected stimulator cells, supernatants of cocultures from T cell hybridomas and stimulators were collected 24 h postinfection and analyzed by IL-2 ELISA (BD Pharmingen).…”

Section: Lacz Assaymentioning

confidence: 99%

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

Basler

Lauer

Moebius

et al. 2012

The Journal of Immunology

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The proteasome is responsible for the generation of most epitopes presented on MHC class I molecules. Treatment of cells with IFN-γ leads to the replacement of the constitutive catalytic subunits β1, β2, and β5 by the inducible subunits low molecular mass polypeptide (LMP) 2 (β1i), multicatalytic endopeptidase complex-like-1 (β2i), and LMP7 (β5i), respectively. The incorporation of these subunits is required for the production of numerous MHC class I-restricted T cell epitopes. The structural features rather than the proteolytic activity of an immunoproteasome subunit are needed for the generation of some epitopes, but the underlying mechanisms have remained elusive. Experiments with LMP2-deficient splenocytes revealed that the generation of the male HY-derived CTL-epitope UTY246–254 was dependent on LMP2. Treatment of male splenocytes with an LMP2-selective inhibitor did not reduce UTY246–254 presentation, whereas silencing of β1 activity increased presentation of UTY246–254. In vitro degradation experiments showed that the caspase-like activity of β1 was responsible for the destruction of this CTL epitope, whereas it was preserved when LMP2 replaced β1. Moreover, inhibition of the β5 subunit rescued the presentation of the influenza matrix 58–66 epitope, thus suggesting that a similar mechanism can apply to the exchange of β5 by LMP7. Taken together, our data provide a rationale why the structural property of an immunoproteasome subunit rather than its activity is required for the generation of a CTL epitope.

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Section: Lacz Assaymentioning

confidence: 99%

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

Basler

Lauer

Moebius

et al. 2012

The Journal of Immunology

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“…Epoxomicin (Sigma) blocks the proteasomal machinery irreversibly by inhibiting primarily chymotrypsin-like, but also trypsin-like, and peptidylglutamyl peptide-hydrolyzing activities of the proteasome [48]. Thus, it interferes with production of proteasome-dependent MHC-I ligands [49]. …”

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confidence: 99%

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

et al. 2013

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Hantaviruses are emerging human pathogens. They induce an unusually strong antiviral response of human HLA class I (HLA-I) restricted CD8 + T cells that may contribute to tissue damage and hantavirus-associated disease. In this study, we analyzed possible hantaviral mechanisms that enhance the HLA-I antigen presentation machinery. Upon hantavirus infection of various human and primate cell lines, we observed transactivation of promoters controlling classical HLA molecules. Hantavirus-induced HLA-I upregulation required proteasomal activity and was associated with increased TAP expression. Intriguingly, human DCs acquired the capacity to cross-present antigen upon hantavirus infection. Furthermore, knockdown of TIR domain containing adaptor inducing IFN-β or retinoic acid inducible gene I abolished hantavirus-driven HLA-I induction. In contrast, MyD88-dependent viral sensors were not involved in HLA-I induction. Our results show that hantaviruses strongly boost the HLA-I antigen presentation machinery by mechanisms that are dependent on both retinoic acid inducible gene I and TIR domain containing adaptor inducing IFN-β.Keywords: Antigen presentation/processing · Cross-presentation/priming · Immunopathology · Infectious diseases · Innate immunity IntroductionRapidly changing ecosystems and climate facilitate the emergence of human infections with hantaviruses [1][2][3]. In Germany, increasing numbers of hantavirus-associated disease cases have been observed [4]. The enhanced health hazard emanating from pathogenic hantavirus species has been recognized by the German National Health Institute, which has recently reprioritized infecCorrespondence: Prof. Günther Schönrich e-mail: guenther.schoenrich@charite.de tious pathogens and placed hantaviruses in the highest priority group [5].Hantaviruses belong to the family Bunyaviridae and have segmented genomes [6]. The three viral RNA segments code for a nucleoprotein (N), two glycoproteins (Gn and Gc), and a RNA-dependent RNA polymerase. Hantaviruses are transmitted to humans by inhalation of virus-containing aerosols that are derived from the excreta of hantavirus-infected rodents. These natural reservoir hosts remain asymptomatic, although they are persistently infected. In striking contrast, hantaviruses are eliminated in humans at the cost of severe symptoms such as pulmonary or renal failure. Currently, no suitable vaccines or therapeutics are C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2566-2576 Antigen processing 2567 available for prevention or treatment of human hantavirus infections [7,8].Hantaviruses are not directly cytopathic for infected cells, suggesting that the antiviral immune response itself causes hantavirus-associated syndromes [9,10]. In accordance, hantaviruses trigger an unusually potent reaction of CD8 + T lymphocytes, that is devoid of regulatory T cells, and still detectable years after resolution [11][12][13][14]. Human CD8 + T cells are stimulated by HLA class I (HLA-I) molecules that prese...

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“…These findings altogether indicated that the restoration of 2B2-CTL recognition by pretreatment with bortezomib especially in combination with IFN-g is not due to E6 mRNA up-regulation, but rather is likely caused by modulation of proteasomal function by bortezomib, as reported previously. [11][12][13] HLA-A*2402-restricted E6 49-57 -specific CD81 T cells can be induced from CIN and cervical cancer patients despite low precursor frequencies Identification of the immunogenic HLA-A*2402-restricted HPV-16 E6-derived epitope enabled us to synthesize the HLA-A24/E6 [49][50][51][52][53][54][55][56][57] tetramer, which clearly stained 2B2-CTL (Fig. 6a, right panel) and detected a growing population of E6 [49][50][51][52][53][54][55][56][57] -specific T cells in bulk culture after stimulation from which 2B2-CTL was generated (Fig.…”

Section: Treatment Of Cervical Cancer Cell Lines With Proteasome Inhimentioning

confidence: 99%

“…Since presentation of certain CTL epitopes of tumor and viral antigens is reported to be enhanced by treatment of target cells with proteasome inhibitors, [11][12][13] we first attempted to sensitize SiHa cells with epoxomicin or bortezomib. Epoxomicin is an irreversible proteasome inhibitor, which is about 100-fold more potent than lactacystin, 12 while bortezomib is a reversible proteasome inhibitor. 15 As shown in Figure 3a, treatment of SiHa cells with epoxomicin or bortezomib induced IFN-g production from 2B2-CTL but not from an irrelevant CTL clone or SiHa cells themselves.…”

Section: Treatment Of Cervical Cancer Cell Lines With Proteasome Inhimentioning

confidence: 99%

“…Thus, inhibition of proteasome functions by inhibitors can cause not only cellular apoptosis by affecting cellular regulatory proteins, 10 but also modulation of the generation of some antigenic peptides by proteasomes, leading to loss or gain of antigenicity. [11][12][13] Among various proteasome inhibitors, bortezomib, a boronic acid dipeptide, is the only one to have progressed to clinical trials in cancer patients, and has shown striking activity in patients with advanced multiple myeloma. 14 Bortezomib is a selective but reversible inhibitor of both standard proteasomes and immunoproteasomes.…”

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Identification of an HLA‐A24‐restricted cytotoxic T lymphocyte epitope from human papillomavirus type‐16 E6: The combined effects of bortezomib and interferon‐γ on the presentation of a cryptic epitope

Akatsuka

Nawa

Kondo

et al. 2006

Intl Journal of Cancer

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About 50% of cervical cancers are associated with human papillomavirus type 16 (HPV-16), and since the HPV-16 E6 and E7 oncoproteins are constitutively expressed in the tumor cells, they are attractive targets for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. Nevertheless, only a limited number of HPV-16 E6 epitopes have been identified to date. Using reverse immunological methods, we have generated a CTL clone against the HPV-16 E6 49-57 epitope restricted by HLA-A*2402, which is the most common allele in Japan and relatively frequent worldwide, capable of lysing 293T cells transduced with HLA-A*2402 and HPV-16 E6. Although it was unable to recognize the SiHa cervical cancer cell line positive for HPV-16 and HLA-A*2402, the cells became susceptible to lysis when transduced with E6-E7 genes, which was unexpectedly offset by pretreatment with interferon (IFN)-c alone. Interestingly, however, combined pretreatment with a proteasome inhibitor, bortezomib and IFN-c fully restored CTL-mediated lysis of the original SiHa cells. Furthermore, such intervention of 2 of 4 other cervical cancer cell lines expressing HPV-16 E6 and HLA-A*2402 was found to induce IFN-c production by specific CTLs. Tetramer analysis further revealed that induction of E6 49-57 -specific T cells was possible in 5 of 7 patients with HPV-16-positive high grade cervical intraepithelial neoplasia or cervical cancer by in vitro stimulation with E6 49-57 peptide. Thus, these findings together indicate that E6 49-57 is a candidate epitope for immunotherapy and immunological monitoring of such patients. ' 2006 Wiley-Liss, Inc.Key words: cytotoxic T lymphocyte; tumor immunity; epitope, cervical neoplasm; bortezomib Cervical cancer, the second most common cancer in women worldwide, with 250,000 new cases diagnosed each year, 1 is causally linked with human papillomavirus (HPV), the first proposed necessary cause of a human cancer as assessed by the World Health Organization. 2 High-risk HPV-16 is the most common type in all countries, with an overall prevalence of more than 50% in cervical cancers, 3 and 42.4% in Japanese patients. 4 Approximately 95% of HPV infections of the anogenital tract resolve spontaneously because of immune responses, 5 and the risk of cervical cancer is markedly increased in patients with immunodeficiency. [6][7][8] These findings suggest that the immune system plays a pivotal role in preventing development and progression of cervical cancer.Two HPV oncoproteins, E6 and E7, which can inhibit the tumor suppressors, p53 and RB respectively, are constitutively expressed in cervical cancer cells and appear to be required to maintain their malignant growth. 9 These viral oncoproteins, which are not present in normal cells, have been considered to be attractive targets for specific immunotherapy against cervical cancer, and identification and characterization of cytotoxic T lymphocyte (CTL) epitopes for HPV have facilitated the development of peptide vaccines against cervical cancer. Most of the CTL epitopes identified to date ...

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The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses

Cited by 95 publications

References 54 publications

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

Identification of an HLA‐A24‐restricted cytotoxic T lymphocyte epitope from human papillomavirus type‐16 E6: The combined effects of bortezomib and interferon‐γ on the presentation of a cryptic epitope

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