MHC class I pathway Dotaz Zobrazit nápovědu
The accumulation of protein aggregates is toxic and linked to different diseases such as neurodegenerative disorders, but the role of the immune system to target and destroy aggregate-carrying cells is still relatively unknown. Here we show a substrate-specific presentation of antigenic peptides to the direct MHC class I pathway via autophagy. We observed no difference in presentation of peptides derived from the viral EBNA1 protein following suppression of autophagy by knocking down Atg5 and Atg12. However, the same knock down treatment suppressed the presentation from ovalbumin. Fusing the aggregate-prone poly-glutamine (PolyQ) to the ovalbumin had no effect on antigen presentation via autophagy. Interestingly, fusing the EBNA1-derived gly-ala repeat (GAr) sequence to ovalbumin rendered the presentation Atg5/12 independent. We also demonstrate that the relative levels of protein expression did not affect autophagy-mediated antigen presentation. These data suggest a substrate-dependent presentation of antigenic peptides for the MHC class I pathway via autophagy and indicate that the GAr of the EBNA1 illustrates a novel virus-mediated mechanism for immune evasion of autophagy-dependent antigen presentation.
MHC class I presentation of short peptides enables CD8+ T cell (TCD8+) immunosurveillance of tumors and intracellular pathogens. A key feature of the class I pathway is that the immunopeptidome is highly skewed from the cellular degradome, indicating high selectivity of the access of protease-generated peptides to class I molecules. Similarly, in professional antigen-presenting cells, peptides from minute amounts of proteins introduced into the cytosol outcompete an overwhelming supply of constitutively generated peptides. Here, we propose that antigen processing is based on substrate channeling and review recent studies from the antigen processing and cell biology fields that provide a starting point for testing this hypothesis.
- MeSH
- adaptivní imunita imunologie MeSH
- antigen prezentující buňky imunologie MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- imunitní dozor imunologie MeSH
- lidé MeSH
- MHC antigeny I. třídy imunologie MeSH
- peptidy imunologie MeSH
- prezentace antigenu imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Intramural MeSH
The source of peptides that enter the major histocompatibility class I (MHCI) pathway has been intensively debated over the last two decades. The initial assumption that peptides are derived from degradation of full length proteins was challenged by a model in which alternative translation products are a source of peptides. This model has been tested and supported by scientific data. We now need new hypotheses on the physiological implications of different sources of peptides for the MHCI pathway. The aim of this overview is to give an up-to-date account of the source of antigenic peptide material for the MHCI pathway and to incorporate the more recent observations of alternative mRNA translation products into existing models of the direct and cross-presentation pathways.
BACKGROUND: Epigenetic mechanisms have important roles in the tumour escape from immune responses, such as in MHC class I downregulation or altered expression of other components involved in antigen presentation. Chemotherapy with DNA methyltransferase inhibitors (DNMTi) can thus influence the tumour cell interactions with the immune system and their sensitivity to immunotherapy. METHODS: We evaluated the therapeutic effects of the DNMTi 5-azacytidine (5AC) against experimental MHC class I-deficient and -positive tumours. The 5AC therapy was combined with immunotherapy, using a murine model for HPV16-associated tumours. RESULTS: We have demonstrated 5AC additive effects against MHC class I-positive and -deficient tumours when combined with unmethylated CpG oligodeoxynucleotides or with IL-12-producing cellular vaccine. The efficacy of the combined chemoimmunotherapy against originally MHC class I-deficient tumours was partially dependent on the CD8(+)-mediated immune responses. Increased cell surface expression of MHC class I cell molecules, associated with upregulation of the antigen-presenting machinery-related genes, as well as of genes encoding selected components of the IFNγ-signalling pathway in tumours explanted from 5AC-treated animals, were observed. CONCLUSION: Our data suggest that chemotherapy of MHC class I-deficient tumours with 5AC combined with immunotherapy is an attractive setting in the treatment of MHC class I-deficient tumours.
- MeSH
- azacytidin farmakologie MeSH
- DNA primery MeSH
- ELISA MeSH
- experimentální nádory farmakoterapie imunologie terapie virologie MeSH
- imunoterapie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- lidský papilomavirus 16 izolace a purifikace MeSH
- metylace MeSH
- MHC antigeny I. třídy imunologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- protinádorové antimetabolity farmakologie MeSH
- sekvence nukleotidů MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Downregulation of MHC class I expression on tumour cells, a common mechanism by which tumour cells can escape from specific immune responses, can be associated with coordinated silencing of antigen-presenting machinery genes. The expression of these genes can be restored by IFNγ. In this study we documented association of DNA demethylation of selected antigen-presenting machinery genes located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells in several MHC class I-deficient murine tumour cell lines (TC-1/A9, TRAMP-C2, MK16 and MC15). Our data also documented higher methylation levels in these genes in TC-1/A9 cells, as compared to their parental MHC class I-positive TC-1 cells. IFNγ-mediated DNA demethylation was relatively fast in comparison with demethylation induced by DNA methyltransferase inhibitor 5-azacytidine, and associated with increased histone H3 acetylation in the promoter regions of APM genes. Comparative transcriptome analysis in distinct MHC class I-deficient cell lines upon their treatment with either IFNγ or epigenetic agents revealed that a set of genes, significantly enriched for the antigen presentation pathway, was regulated in the same manner. Our data demonstrate that IFNγ acts as an epigenetic modifier when upregulating the expression of antigen-presenting machinery genes.
- MeSH
- down regulace MeSH
- epigeneze genetická MeSH
- fibrosarkom genetika imunologie metabolismus MeSH
- geny MHC třídy I * MeSH
- interferon gama genetika imunologie metabolismus MeSH
- metylace DNA * MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- prezentace antigenu genetika MeSH
- regulace genové exprese u nádorů MeSH
- signální transdukce MeSH
- transfekce MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- exprese genu imunologie MeSH
- melanom experimentální imunologie MeSH
- mezibuněčná komunikace imunologie MeSH
- MHC antigeny I. třídy genetika chemie imunologie MeSH
- receptor inzulinu imunologie MeSH
- receptory růstových faktorů imunologie MeSH
- signální transdukce imunologie MeSH
- Publikační typ
- přehledy MeSH
The notion that alternative peptide substrates can be processed and presented to the MHC class I pathway has opened for new aspects on how the immune system detects infected or damaged cells. Recent works show that antigenic peptides are derived from intron sequences in pre-mRNAs target for the nonsense-mediated degradation pathway. Introns are spliced out co-transcriptionally suggesting that such pioneer translation products (PTPs) are synthesized on the nascent RNAs in the nuclear compartment to ensure that the first peptides to emerge from an mRNA are destined for the class I pathway. This illustrates an independent translation event during mRNA maturation that give rise to specific peptide products with a specific function in the immune system. The characterization of the translation apparatus responsible for PTP synthesis will pave the way for understanding how PTP production is regulated in different tissues under different conditions and will help designing new vaccine strategies.
- MeSH
- buněčné jádro genetika imunologie MeSH
- CD8-pozitivní T-lymfocyty cytologie imunologie MeSH
- cytosol imunologie metabolismus MeSH
- dendritické buňky cytologie imunologie metabolismus MeSH
- fagozomy genetika imunologie MeSH
- introny MeSH
- lidé MeSH
- MHC antigeny I. třídy genetika imunologie MeSH
- peptidy genetika imunologie MeSH
- prekurzory RNA genetika imunologie MeSH
- prezentace antigenu genetika MeSH
- proteasomový endopeptidasový komplex genetika imunologie MeSH
- proteosyntéza imunologie MeSH
- sestřih RNA imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Epigenetic events play an important role in tumour progression and also contribute to escape of the tumour from immune surveillance. In this study, we investigated the up-regulation of major histocompatibility complex (MHC) class I surface expression on tumour cells by epigenetic mechanisms using a murine tumour cell line expressing human E6 and E7 human papilloma virus 16 (HPV16) oncogenes and deficient in MHC class I expression, as a result of impaired antigen-presenting machinery (APM). Treatment of the cells with the histone deacetylase inhibitor Trichostatin A, either alone or in combination with the DNA demethylating agent 5-azacytidine, induced surface re-expression of MHC class I molecules. Consequently, the treated cells became susceptible to lysis by specific cytotoxic T lymphocytes. Further analysis revealed that epigenetic induction of MHC class I surface expression was associated with the up-regulation of APM genes [transporter associated with antigen processing 1 (TAP-1), TAP-2, low-molecular-mass protein 2 (LMP-2) and LMP-7]. The results demonstrate that expression of the genes involved in APM are modulated by epigenetic mechanisms and suggest that agents modifying DNA methylation and/or histone acetylation have the potential to change the effectiveness of antitumour immune responses and therapeutically may have an impact on immunological output.
- MeSH
- apoptóza účinky léků MeSH
- azacytidin farmakologie MeSH
- epigeneze genetická imunologie MeSH
- experimentální nádory genetika imunologie virologie MeSH
- financování organizované MeSH
- geny MHC třídy I MeSH
- histony metabolismus MeSH
- infekce papilomavirem komplikace MeSH
- inhibitory enzymů farmakologie MeSH
- kyseliny hydroxamové farmakologie MeSH
- lidé MeSH
- lidský papilomavirus 16 MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- polymerázová řetězová reakce s reverzní transkripcí metody MeSH
- prezentace antigenu genetika imunologie MeSH
- upregulace genetika imunologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.
- MeSH
- celogenomová asociační studie metody MeSH
- genetická heterogenita MeSH
- heterozygot MeSH
- lidé MeSH
- MHC antigeny I. třídy genetika MeSH
- MHC antigeny II. třídy genetika MeSH
- nehodgkinský lymfom genetika MeSH
- prospektivní studie MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
