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Immune escape strategies of a contagious cancer, devil facial tumour disease
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Abstracts / Molecular Immunology 51 (2012) 5–41
Intracellular trafficking of the human invariant chain isoforms, Iip33 and Iip35
Immune escape strategies of a contagious cancer, devil facial tumour disease
Kine Marita Knudsen Sand ∗ , Ole Landsverk, Oddmund Bakke, Tone Gregers
Hannah Siddle a,∗ , Alexandre Kreiss b , Cesar Tovab b , YuanYuan Cheng c , Katherine Belov c , Kate Swift d , Anne-Maree Pearse d , Karsten Skjodt e , Gregory Woods b , Jim Kaufman f
Institute of Molecular Biosciences and Centre for Immune Regulation, University of Oslo, Norway
a
University of Cambridge, Department of Pathology University of Tasmania c University of Sydney d Department of Primary Industries and Water/Animal Health Laboratory e University of South Denmark f University of Cambridge b
The invariant chain (Ii) has for many years been known to have important functions in MHC class II antigen presentation. There are four isoforms of Ii in humans: Iip33, Iip35, Iip41 and Iip43. The two shorter isoforms (Iip33 and Iip35) are formed due to two alternative translational start sites, and Iip35 contains an N-terminal extension of 16 aa compared to Iip33. This 16 aa N-terminal extension contains a strong ER retention motif. The Iip41 and Iip43 isoforms have the same N-terminal ends as Iip33 and Iip35 respectively, but in addition they contain an extra exon. Being the predominant isoform Iip33 is studied most extensively, while limited data is available on the human specific isoforms. In this work both imaging and different biochemical techniques were used to study Iip33 and Iip35, both individually and coexpressed. The Ii isoforms associate randomly into heterotrimers in the endoplasmic reticulum (ER). Our results indicate that the two isoforms behave differently when co-expressed, compared to when expressed alone. Iip33 function is highly affected by the presence of Iip35. Iip35 leads to ER retention of Ii heterotrimers. Consequently Iip33 trafficking through the secretory pathway is delayed, and its half-life is significantly increased in the presence of Iip35. The formation of Ii-induced enlarged endosomal vesicles (ILEVs) which is normally observed upon over-expression of Iip33, is not observed upon co-expression with Iip35. Iip35 is also affected by the presence of Iip33 as the half-life of Iip35 is decreased in the presence of Iip33. This suggests a more efficient endosomal sorting of Iip35 in the presence of Iip33. Our results indicate that Iip35 has a large influence on the total pool of Ii even when present in low levels. The properties of Iip35 and the effects of its presence in Ii heterotrimers are thus important to understand MHC class II antigen presentation in humans. doi:10.1016/j.molimm.2012.02.081 A novel transfer RNA shapes the cryptic peptide repertoire presented by MHC class I molecules Nilabh Shastri a,∗ , Shelley Starck a , Vivian Jiang a , Mariana PavonEternod b , Sharanya Prasad a , Brian McCarthy a , Tao Pan b a b
University of California, Berkeley University of Chicago
Effective immune surveillance by cytotoxic T cells requires newly synthesized polypeptides for presentation by MHC class I molecules. In normal as well as virus infected or transformed cells, the polypeptides are produced from conventional AUG as well as cryptic non-AUG initiated reading frames by distinct but poorly understood translational mechanisms. By biochemical analysis of ribosomes bound to CUG or AUG initiation codons we show here that cells used a novel elongator tRNA to initiate translation at cryptic CUG codons. The CUG/Leu-tRNA initiation is independent of the conventional AUG/Met-tRNA pathway but requires expression of a novel initiation factor, eIF2A. Thus, a tRNA based translational mechanism supplies peptides for presentation by MHC I and could also regulate non-AUG-initiated global protein synthesis. doi:10.1016/j.molimm.2012.02.082
A contagious cancer, devil facial tumour disease (DFTD), has emerged in the Tasmanian devil, a carnivorous marsupial endemic to the island of Tasmania. DFTD cells pass between individuals during biting behaviour and once transmitted divide rapidly, resulting in the development of tumours around the face and neck. Despite an efficient immune system DFTD does not elicit a protective immune response from host devils, resulting in 100% mortality of affected animals and the rapid decline of the species. As a malignant and foreign cell, DFTD should activate host T lymphocytes via foreign major histocompatibility complex (MHC) class I molecules on the surface of tumour cells. How DFTD remains consistently concealed from immune cells is not yet understood. Here we show that DFTD cells express functional MHC class I (MHCI) and class II B (MHCIIB) transcripts but little or no RNA for genes essential for antigen processing, including 2-microglobulin (2-m), the transporters associated with antigen processing (TAPs), MHC class II A (MHCIIA) and DMB. We demonstrate only trace amounts of MHCI protein at the surface of DFTD cells both in vitro and in vivo, which can explain how DFTD avoids the T cell response. However, MHCI protein can be restored in vitro by epigenetic manipulation and cytokine treatment, suggesting that regulatory rather than structural mutations are responsible for down regulation of MHCI protein. Moreover, these results suggest that epigenetic control has played a role in the emergence of DFTD and might allow the expression of MHCI molecules to vary depending on circumstances. Such tuning could afford an evolutionary advantage for long lived, transmissible tumours such as DFTD and the only other example, canine transmissible venereal tumour (CTVT). These results provide both a molecular basis for how contagious cancers can pass between individuals without detection and a potential vaccine strategy against DFTD. doi:10.1016/j.molimm.2012.02.083 Proteasome immunosubunits protect against the development of CD8 T-cell-mediated autoimmune diseases ¨ a , Benedicte Lie b , Dietmar Zaiss a , Cornelis Bekker a , Andrea Grne Alice Sijts a,∗ a b
Utrecht University Institute of Immunology, Oslo University Hospital Rikshospitale
Exposure of cells to inflammatory cytokines induces the expression of three proteasome immunosubunits, two of which are encoded in the MHC-II region. The induced subunits replace their constitutive homologues in newly formed, so called immunoproteasomes. Immunosubunit incorporation enhances the proteasome’ proteolytic activity and modifies the proteasome’ cleavage site preferences, which improves the generation of many MHC-I presented peptides and shapes the fine-specificity of pathogen-specific CD8 T cell responses. We here report on a second effect of immunoproteasome formation on CD8 T cell responses.
Abstracts / Molecular Immunology 51 (2012) 5–41
Intracellular trafficking of the human invariant chain isoforms, Iip33 and Iip35
Immune escape strategies of a contagious cancer, devil facial tumour disease
Kine Marita Knudsen Sand ∗ , Ole Landsverk, Oddmund Bakke, Tone Gregers
Hannah Siddle a,∗ , Alexandre Kreiss b , Cesar Tovab b , YuanYuan Cheng c , Katherine Belov c , Kate Swift d , Anne-Maree Pearse d , Karsten Skjodt e , Gregory Woods b , Jim Kaufman f
Institute of Molecular Biosciences and Centre for Immune Regulation, University of Oslo, Norway
a
University of Cambridge, Department of Pathology University of Tasmania c University of Sydney d Department of Primary Industries and Water/Animal Health Laboratory e University of South Denmark f University of Cambridge b
The invariant chain (Ii) has for many years been known to have important functions in MHC class II antigen presentation. There are four isoforms of Ii in humans: Iip33, Iip35, Iip41 and Iip43. The two shorter isoforms (Iip33 and Iip35) are formed due to two alternative translational start sites, and Iip35 contains an N-terminal extension of 16 aa compared to Iip33. This 16 aa N-terminal extension contains a strong ER retention motif. The Iip41 and Iip43 isoforms have the same N-terminal ends as Iip33 and Iip35 respectively, but in addition they contain an extra exon. Being the predominant isoform Iip33 is studied most extensively, while limited data is available on the human specific isoforms. In this work both imaging and different biochemical techniques were used to study Iip33 and Iip35, both individually and coexpressed. The Ii isoforms associate randomly into heterotrimers in the endoplasmic reticulum (ER). Our results indicate that the two isoforms behave differently when co-expressed, compared to when expressed alone. Iip33 function is highly affected by the presence of Iip35. Iip35 leads to ER retention of Ii heterotrimers. Consequently Iip33 trafficking through the secretory pathway is delayed, and its half-life is significantly increased in the presence of Iip35. The formation of Ii-induced enlarged endosomal vesicles (ILEVs) which is normally observed upon over-expression of Iip33, is not observed upon co-expression with Iip35. Iip35 is also affected by the presence of Iip33 as the half-life of Iip35 is decreased in the presence of Iip33. This suggests a more efficient endosomal sorting of Iip35 in the presence of Iip33. Our results indicate that Iip35 has a large influence on the total pool of Ii even when present in low levels. The properties of Iip35 and the effects of its presence in Ii heterotrimers are thus important to understand MHC class II antigen presentation in humans. doi:10.1016/j.molimm.2012.02.081 A novel transfer RNA shapes the cryptic peptide repertoire presented by MHC class I molecules Nilabh Shastri a,∗ , Shelley Starck a , Vivian Jiang a , Mariana PavonEternod b , Sharanya Prasad a , Brian McCarthy a , Tao Pan b a b
University of California, Berkeley University of Chicago
Effective immune surveillance by cytotoxic T cells requires newly synthesized polypeptides for presentation by MHC class I molecules. In normal as well as virus infected or transformed cells, the polypeptides are produced from conventional AUG as well as cryptic non-AUG initiated reading frames by distinct but poorly understood translational mechanisms. By biochemical analysis of ribosomes bound to CUG or AUG initiation codons we show here that cells used a novel elongator tRNA to initiate translation at cryptic CUG codons. The CUG/Leu-tRNA initiation is independent of the conventional AUG/Met-tRNA pathway but requires expression of a novel initiation factor, eIF2A. Thus, a tRNA based translational mechanism supplies peptides for presentation by MHC I and could also regulate non-AUG-initiated global protein synthesis. doi:10.1016/j.molimm.2012.02.082
A contagious cancer, devil facial tumour disease (DFTD), has emerged in the Tasmanian devil, a carnivorous marsupial endemic to the island of Tasmania. DFTD cells pass between individuals during biting behaviour and once transmitted divide rapidly, resulting in the development of tumours around the face and neck. Despite an efficient immune system DFTD does not elicit a protective immune response from host devils, resulting in 100% mortality of affected animals and the rapid decline of the species. As a malignant and foreign cell, DFTD should activate host T lymphocytes via foreign major histocompatibility complex (MHC) class I molecules on the surface of tumour cells. How DFTD remains consistently concealed from immune cells is not yet understood. Here we show that DFTD cells express functional MHC class I (MHCI) and class II B (MHCIIB) transcripts but little or no RNA for genes essential for antigen processing, including 2-microglobulin (2-m), the transporters associated with antigen processing (TAPs), MHC class II A (MHCIIA) and DMB. We demonstrate only trace amounts of MHCI protein at the surface of DFTD cells both in vitro and in vivo, which can explain how DFTD avoids the T cell response. However, MHCI protein can be restored in vitro by epigenetic manipulation and cytokine treatment, suggesting that regulatory rather than structural mutations are responsible for down regulation of MHCI protein. Moreover, these results suggest that epigenetic control has played a role in the emergence of DFTD and might allow the expression of MHCI molecules to vary depending on circumstances. Such tuning could afford an evolutionary advantage for long lived, transmissible tumours such as DFTD and the only other example, canine transmissible venereal tumour (CTVT). These results provide both a molecular basis for how contagious cancers can pass between individuals without detection and a potential vaccine strategy against DFTD. doi:10.1016/j.molimm.2012.02.083 Proteasome immunosubunits protect against the development of CD8 T-cell-mediated autoimmune diseases ¨ a , Benedicte Lie b , Dietmar Zaiss a , Cornelis Bekker a , Andrea Grne Alice Sijts a,∗ a b
Utrecht University Institute of Immunology, Oslo University Hospital Rikshospitale
Exposure of cells to inflammatory cytokines induces the expression of three proteasome immunosubunits, two of which are encoded in the MHC-II region. The induced subunits replace their constitutive homologues in newly formed, so called immunoproteasomes. Immunosubunit incorporation enhances the proteasome’ proteolytic activity and modifies the proteasome’ cleavage site preferences, which improves the generation of many MHC-I presented peptides and shapes the fine-specificity of pathogen-specific CD8 T cell responses. We here report on a second effect of immunoproteasome formation on CD8 T cell responses.