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Article ; Online: Diabetes risk loci-associated pathways are shared across metabolic tissues.

Bouland, Gerard A / Beulens, Joline W J / Nap, Joey / van der Slik, Arno R / Zaldumbide, Arnaud / 't Hart, Leen M / Slieker, Roderick C

BMC genomics

2022 Volume 23, Issue 1, Page(s) 368

Abstract: Aims/hypothesis: Numerous genome-wide association studies have been performed to understand the influence of genetic variation on type 2 diabetes etiology. Many identified risk variants are located in non-coding and intergenic regions, which complicates ...

Abstract	Aims/hypothesis: Numerous genome-wide association studies have been performed to understand the influence of genetic variation on type 2 diabetes etiology. Many identified risk variants are located in non-coding and intergenic regions, which complicates understanding of how genes and their downstream pathways are influenced. An integrative data approach will help to understand the mechanism and consequences of identified risk variants. Methods: In the current study we use our previously developed method CONQUER to overlap 403 type 2 diabetes risk variants with regulatory, expression and protein data to identify tissue-shared disease-relevant mechanisms. Results: One SNP rs474513 was found to be an expression-, protein- and metabolite QTL. Rs474513 influenced LPA mRNA and protein levels in the pancreas and plasma, respectively. On the pathway level, in investigated tissues most SNPs linked to metabolism. However, in eleven of the twelve tissues investigated nine SNPs were linked to differential expression of the ribosome pathway. Furthermore, seven SNPs were linked to altered expression of genes linked to the immune system. Among them, rs601945 was found to influence multiple HLA genes, including HLA-DQA2, in all twelve tissues investigated. Conclusion: Our results show that in addition to the classical metabolism pathways, other pathways may be important to type 2 diabetes that show a potential overlap with type 1 diabetes.
MeSH term(s)	Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 2/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2022-05-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-022-08587-5
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Article ; Online: IFNɣ but not IFNα increases recognition of insulin defective ribosomal product-derived antigen to amplify islet autoimmunity.

Thomaidou, Sofia / Munoz Garcia, Amadeo / de Lange, Sabine / Gan, Jin / van der Slik, Arno R / Hoeben, Rob C / Roep, Bart O / Carlotti, Françoise / Zaldumbide, Arnaud

Diabetologia

2023 Volume 66, Issue 11, Page(s) 2075–2086

Abstract: Aims/hypothesis: The inflammatory milieu characteristic of insulitis affects translation fidelity and generates defective ribosomal products (DRiPs) that participate in autoimmune beta cell destruction in type 1 diabetes. Here, we studied the role of ... ...

Abstract	Aims/hypothesis: The inflammatory milieu characteristic of insulitis affects translation fidelity and generates defective ribosomal products (DRiPs) that participate in autoimmune beta cell destruction in type 1 diabetes. Here, we studied the role of early innate cytokines (IFNα) and late immune adaptive events (IFNɣ) in insulin DRiP-derived peptide presentation to diabetogenic CD8+ T cells. Methods: Single-cell transcriptomics of human pancreatic islets was used to study the composition of the (immuno)proteasome. Specific inhibition of the immunoproteasome catalytic subunits was achieved using siRNA, and antigenic peptide presentation at the cell surface of the human beta cell line EndoC-βH1 was monitored using peptide-specific CD8 T cells. Results: We found that IFNγ induces the expression of the PSMB10 transcript encoding the β2i catalytic subunit of the immunoproteasome in endocrine beta cells, revealing a critical role in insulin DRiP-derived peptide presentation to T cells. Moreover, we showed that PSMB10 is upregulated in a beta cell subset that is preferentially destroyed in the pancreases of individuals with type 1 diabetes. Conclusions/interpretation: Our data highlight the role of the degradation machinery in beta cell immunogenicity and emphasise the need for evaluation of targeted immunoproteasome inhibitors to limit beta cell destruction in type 1 diabetes. Data availability: The single-cell RNA-seq dataset is available from the Gene Expression Omnibus (GEO) using the accession number GSE218316 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE218316 ).
MeSH term(s)	Humans ; Insulin/metabolism ; Diabetes Mellitus, Type 1/metabolism ; Autoimmunity ; Islets of Langerhans/metabolism ; Interferon-alpha/pharmacology ; Insulin-Secreting Cells/metabolism ; Interferon-gamma/pharmacology ; Interferon-gamma/metabolism
Chemical Substances	Insulin ; Interferon-alpha ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2023-08-15
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-023-05991-8
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Article ; Online: Presence of immunogenic alternatively spliced insulin gene product in human pancreatic delta cells.

van Tienhoven, René / Kracht, Maria J L / van der Slik, Arno R / Thomaidou, Sofia / Wolters, Anouk H G / Giepmans, Ben N G / Riojas, Juan Pablo Romero / Nelson, Michael S / Carlotti, Françoise / de Koning, Eelco J P / Hoeben, Rob C / Zaldumbide, Arnaud / Roep, Bart O

Diabetologia

2023 Volume 66, Issue 5, Page(s) 884–896

Abstract: Aims/hypothesis: Transcriptome analyses revealed insulin-gene-derived transcripts in non-beta endocrine islet cells. We studied alternative splicing of human INS mRNA in pancreatic islets.: Methods: Alternative splicing of insulin pre-mRNA was ... ...

Abstract	Aims/hypothesis: Transcriptome analyses revealed insulin-gene-derived transcripts in non-beta endocrine islet cells. We studied alternative splicing of human INS mRNA in pancreatic islets. Methods: Alternative splicing of insulin pre-mRNA was determined by PCR analysis performed on human islet RNA and single-cell RNA-seq analysis. Antisera were generated to detect insulin variants in human pancreatic tissue using immunohistochemistry, electron microscopy and single-cell western blot to confirm the expression of insulin variants. Cytotoxic T lymphocyte (CTL) activation was determined by MIP-1β release. Results: We identified an alternatively spliced INS product. This variant encodes the complete insulin signal peptide and B chain and an alternative C-terminus that largely overlaps with a previously identified defective ribosomal product of INS. Immunohistochemical analysis revealed that the translation product of this INS-derived splice transcript was detectable in somatostatin-producing delta cells but not in beta cells; this was confirmed by light and electron microscopy. Expression of this alternatively spliced INS product activated preproinsulin-specific CTLs in vitro. The exclusive presence of this alternatively spliced INS product in delta cells may be explained by its clearance from beta cells by insulin-degrading enzyme capturing its insulin B chain fragment and a lack of insulin-degrading enzyme expression in delta cells. Conclusions/interpretation: Our data demonstrate that delta cells can express an INS product derived from alternative splicing, containing both the diabetogenic insulin signal peptide and B chain, in their secretory granules. We propose that this alternative INS product may play a role in islet autoimmunity and pathology, as well as endocrine or paracrine function or islet development and endocrine destiny, and transdifferentiation between endocrine cells. INS promoter activity is not confined to beta cells and should be used with care when assigning beta cell identity and selectivity. Data availability: The full EM dataset is available via www.nanotomy.org (for review: http://www.nanotomy.org/OA/Tienhoven2021SUB/6126-368/ ). Single-cell RNA-seq data was made available by Segerstolpe et al [13] and can be found at https://sandberglab.se/pancreas . The RNA and protein sequence of INS-splice was uploaded to GenBank (BankIt2546444 INS-splice OM489474).
MeSH term(s)	Humans ; Somatostatin-Secreting Cells/metabolism ; Insulysin/metabolism ; Insulin/genetics ; Insulin/metabolism ; Islets of Langerhans/metabolism ; RNA ; Protein Sorting Signals
Chemical Substances	Insulysin (EC 3.4.24.56) ; Insulin ; RNA (63231-63-0) ; Protein Sorting Signals
Language	English
Publishing date	2023-03-08
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-023-05882-y
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Article ; Online: CONQUER: an interactive toolbox to understand functional consequences of GWAS hits.

Bouland, Gerard A / Beulens, Joline W J / Nap, Joey / van der Slik, Arno R / Zaldumbide, Arnaud / 't Hart, Leen M / Slieker, Roderick C

NAR genomics and bioinformatics

2020 Volume 2, Issue 4, Page(s) lqaa085

Abstract: Numerous large genome-wide association studies have been performed to understand the influence of genetics on traits. Many identified risk loci are in non-coding and intergenic regions, which complicates understanding how genes and their downstream ... ...

Abstract	Numerous large genome-wide association studies have been performed to understand the influence of genetics on traits. Many identified risk loci are in non-coding and intergenic regions, which complicates understanding how genes and their downstream pathways are influenced. An integrative data approach is required to understand the mechanism and consequences of identified risk loci. Here, we developed the R-package CONQUER. Data for SNPs of interest are acquired from static- and dynamic repositories (build GRCh38/hg38), including GTExPortal, Epigenomics Project, 4D genome database and genome browsers. All visualizations are fully interactive so that the user can immediately access the underlying data. CONQUER is a user-friendly tool to perform an integrative approach on multiple SNPs where risk loci are not seen as individual risk factors but rather as a network of risk factors.
Language	English
Publishing date	2020-10-27
Publishing country	England
Document type	Journal Article
ISSN	2631-9268
ISSN (online)	2631-9268
DOI	10.1093/nargab/lqaa085
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Article ; Online: Long RNA Sequencing and Ribosome Profiling of Inflamed β-Cells Reveal an Extensive Translatome Landscape.

Thomaidou, Sofia / Slieker, Roderick C / van der Slik, Arno R / Boom, Jasper / Mulder, Flip / Munoz-Garcia, Amadeo / 't Hart, Leen M / Koeleman, Bobby / Carlotti, Françoise / Hoeben, Rob C / Roep, Bart O / Mei, Hailiang / Zaldumbide, Arnaud

Diabetes

2021 Volume 70, Issue 10, Page(s) 2299–2312

Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of the insulin-producing pancreatic β-cells. Increasing evidence suggest that the β-cells themselves contribute to their own destruction by ... ...

Abstract	Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of the insulin-producing pancreatic β-cells. Increasing evidence suggest that the β-cells themselves contribute to their own destruction by generating neoantigens through the production of aberrant or modified proteins that escape central tolerance. We recently demonstrated that ribosomal infidelity amplified by stress could lead to the generation of neoantigens in human β-cells, emphasizing the participation of nonconventional translation events in autoimmunity, as occurring in cancer or virus-infected tissues. Using a transcriptome-wide profiling approach to map translation initiation start sites in human β-cells under standard and inflammatory conditions, we identify a completely new set of polypeptides derived from noncanonical start sites and translation initiation within long noncoding RNA. Our data underline the extreme diversity of the β-cell translatome and may reveal new functional biomarkers for β-cell distress, disease prediction and progression, and therapeutic intervention in T1D.
MeSH term(s)	Autoimmunity/genetics ; Biomarkers/analysis ; Biomarkers/metabolism ; Cells, Cultured ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/pathology ; Gene Expression Profiling/methods ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Pancreatitis/genetics ; Pancreatitis/metabolism ; Pancreatitis/pathology ; Peptide Chain Initiation, Translational/genetics ; Protein Biosynthesis/genetics ; Protein Processing, Post-Translational ; RNA, Long Noncoding/genetics ; Ribosomes/metabolism ; Sequence Analysis, RNA/methods ; Transcriptome
Chemical Substances	Biomarkers ; RNA, Long Noncoding
Language	English
Publishing date	2021-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db20-1122
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Article ; Online: Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes.

Kracht, Maria J L / van Lummel, Menno / Nikolic, Tatjana / Joosten, Antoinette M / Laban, Sandra / van der Slik, Arno R / van Veelen, Peter A / Carlotti, Françoise / de Koning, Eelco J P / Hoeben, Rob C / Zaldumbide, Arnaud / Roep, Bart O

Nature medicine

2017 Volume 23, Issue 4, Page(s) 501–507

Abstract: Identification of epitopes that are recognized by diabetogenic T cells and cause selective beta cell destruction in type 1 diabetes (T1D) has focused on peptides originating from native beta cell proteins. Translational errors represent a major potential ...

Abstract	Identification of epitopes that are recognized by diabetogenic T cells and cause selective beta cell destruction in type 1 diabetes (T1D) has focused on peptides originating from native beta cell proteins. Translational errors represent a major potential source of antigenic peptides to which central immune tolerance is lacking. Here, we describe an alternative open reading frame within human insulin mRNA encoding a highly immunogenic polypeptide that is targeted by T cells in T1D patients. We show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and we provide direct evidence that such CD8
MeSH term(s)	Adolescent ; Adult ; Autoantigens/genetics ; Autoantigens/immunology ; Autoimmunity/genetics ; Autoimmunity/immunology ; CD8-Positive T-Lymphocytes/immunology ; Child ; Dendritic Cells/immunology ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Female ; HLA-DQ Antigens/immunology ; Humans ; Immunohistochemistry ; Insulin/genetics ; Insulin-Secreting Cells/immunology ; Male ; Open Reading Frames ; Peptides/genetics ; Peptides/immunology ; Protein Biosynthesis ; RNA, Messenger/genetics ; T-Lymphocytes, Cytotoxic/immunology ; Young Adult
Chemical Substances	Autoantigens ; HLA-DQ Antigens ; Insulin ; Peptides ; RNA, Messenger
Language	English
Publishing date	2017-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.4289
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Article: Induction of Treg by monocyte-derived DC modulated by vitamin D₃ or dexamethasone: Differential role for PD-L1

Unger, Wendy W.J / Laban, Sandra / Kleijwegt, Fleur S / van der Slik, Arno R / Roep, Bart O

European journal of immunology. 2009 Nov., v. 39, no. 11

2009

Abstract: Specific therapy with modulated DC may restore immunological tolerance, thereby obviating the need for chronic immunosuppression in transplantation or autoimmunity. In this study we compared the tolerizing capacity of dexamethasone (Dex)- and 1α,25- ... ...

Abstract	Specific therapy with modulated DC may restore immunological tolerance, thereby obviating the need for chronic immunosuppression in transplantation or autoimmunity. In this study we compared the tolerizing capacity of dexamethasone (Dex)- and 1α,25-dihydroxyvitamin D3 (VD3)-modulated DC. Treatment of monocytes with either VD3 or Dex resulted in DC with stable, semi-mature phenotypes compared with standard DC, with intermediate levels of co-stimulatory and MHC class II molecules, which remained unaltered after subsequent pro-inflammatory stimulation. IL-12p70 secretion was lost by VD3- and Dex-DC, whereas IL-10 secretion was unaffected. VD3-DC distinctly produced large amounts of TNF-α. Both VD3- and Dex-DC possessed the capacity to convert CD4 T cells into IL-10-secreting Treg potently suppressing the proliferation of responder T cells. However, only Treg induced by VD3-DC exhibited antigen specificity. VD3-, but not Dex-, DC expressed significant high levels of PD-L1 (programmed death-1 ligand), upon activation. Blockade of PD-L1 during priming redirected T cells to produce IFN-γ instead of IL-10 and abolished acquisition of regulatory capacity. Our findings demonstrate that both VD3- and Dex-DC possess durable but differential tolerogenic features, acting via different mechanisms. Both are potentially useful to specifically down-regulate unwanted immune responses and induce immune tolerance. These modulated DC appear suitable as adjuvant in antigen-specific clinical vaccination intervention strategies.
Language	English
Dates of publication	2009-11
Size	p. 3147-3159.
Publishing place	Wiley-VCH Verlag
Document type	Article
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.200839103
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Article ; Online: Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1.

Unger, Wendy W J / Laban, Sandra / Kleijwegt, Fleur S / van der Slik, Arno R / Roep, Bart O

European journal of immunology

2009 Volume 39, Issue 11, Page(s) 3147–3159

Abstract	Specific therapy with modulated DC may restore immunological tolerance, thereby obviating the need for chronic immunosuppression in transplantation or autoimmunity. In this study we compared the tolerizing capacity of dexamethasone (Dex)- and 1 alpha,25-dihydroxyvitamin D3 (VD3)-modulated DC. Treatment of monocytes with either VD3 or Dex resulted in DC with stable, semi-mature phenotypes compared with standard DC, with intermediate levels of co-stimulatory and MHC class II molecules, which remained unaltered after subsequent pro-inflammatory stimulation. IL-12p70 secretion was lost by VD3- and Dex-DC, whereas IL-10 secretion was unaffected. VD3-DC distinctly produced large amounts of TNF-alpha. Both VD3- and Dex-DC possessed the capacity to convert CD4 T cells into IL-10-secreting Treg potently suppressing the proliferation of responder T cells. However, only Treg induced by VD3-DC exhibited antigen specificity. VD3-, but not Dex-, DC expressed significant high levels of PD-L1 (programmed death-1 ligand), upon activation. Blockade of PD-L1 during priming redirected T cells to produce IFN-gamma instead of IL-10 and abolished acquisition of regulatory capacity. Our findings demonstrate that both VD3- and Dex-DC possess durable but differential tolerogenic features, acting via different mechanisms. Both are potentially useful to specifically down-regulate unwanted immune responses and induce immune tolerance. These modulated DC appear suitable as adjuvant in antigen-specific clinical vaccination intervention strategies.
MeSH term(s)	Anti-Inflammatory Agents/pharmacology ; B7-1 Antigen/immunology ; B7-H1 Antigen ; Cell Differentiation/drug effects ; Cell Differentiation/immunology ; Cell Separation ; Chemotaxis, Leukocyte/immunology ; Cholecalciferol/pharmacology ; Cytokines/biosynthesis ; Cytokines/immunology ; Dendritic Cells/cytology ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dexamethasone/pharmacology ; Flow Cytometry ; Humans ; Immune Tolerance/drug effects ; Immune Tolerance/immunology ; Immunomodulation/immunology ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Membrane Glycoproteins/immunology ; Monocytes/drug effects ; Monocytes/immunology ; Peptides/immunology ; Polymerase Chain Reaction ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Anti-Inflammatory Agents ; B7-1 Antigen ; B7-H1 Antigen ; Cd274 protein, mouse ; Cytokines ; Membrane Glycoproteins ; Peptides ; Cholecalciferol (1C6V77QF41) ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2009-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.200839103
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Article ; Online: Alternative splicing and differential expression of the islet autoantigen IGRP between pancreas and thymus contributes to immunogenicity of pancreatic islets but not diabetogenicity in humans.

de Jong, V Martijn / Abreu, Joana R F / Verrijn Stuart, Annemarie A / van der Slik, Arno R / Verhaeghen, Katrijn / Engelse, Marten A / Blom, Bianca / Staal, Frank J T / Gorus, Frans K / Roep, Bart O

Diabetologia

2013 Volume 56, Issue 12, Page(s) 2651–2658

Abstract: Aims/hypothesis: Thymic expression of self-antigens during T-lymphocyte development is believed to be crucial for preventing autoimmunity. It has been suggested that G6PC2, the gene encoding islet-specific glucose-6-phosphatase catalytic subunit-related ...

Abstract	Aims/hypothesis: Thymic expression of self-antigens during T-lymphocyte development is believed to be crucial for preventing autoimmunity. It has been suggested that G6PC2, the gene encoding islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), is differentially spliced between pancreatic beta cells and the thymus. This may contribute to incomplete elimination of IGRP-specific T lymphocytes in the thymus, predisposing individuals to type 1 diabetes. We tested whether specific splice variation in islets vs thymus correlates with loss of tolerance to IGRP in type 1 diabetes. Methods: Expression of G6PC2 splice variants was compared among thymus, purified medullary thymic epithelial cells and pancreatic islets by RT-PCR. Differential immunogenicity of IGRP splice variants was tested in patients and healthy individuals for autoantibodies and specific cytotoxic T lymphocytes using radiobinding assays and HLA class I multimers, respectively. Results: Previously reported G6PC2 splice variants, including full-length G6PC2, were confirmed, albeit that they occurred in both pancreas and thymus, rather than islets alone. Yet, their expression levels were profoundly greater in islets than in thymus. Moreover, three novel G6PC2 variants were discovered that occur in islets only, leading to protein truncations, frame shifts and neo-sequences prone to immunogenicity. However, autoantibodies to novel or known IGRP splice variants did not differ between patients and healthy individuals, and similar frequencies of IGRP-specific cytotoxic T lymphocytes could be detected in both patients with type 1 diabetes and healthy individuals. Conclusions/interpretation: We propose that post-transcriptional variation of tissue-specific self-proteins may affect negative thymic selection, although this need not necessarily lead to disease.
MeSH term(s)	Alternative Splicing ; Antibody Formation/genetics ; Antibody Formation/immunology ; Autoantigens/immunology ; Autoantigens/metabolism ; Base Sequence ; Diabetes Mellitus, Type 1/enzymology ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Female ; Gene Expression Regulation, Enzymologic ; Genetic Predisposition to Disease ; Glucose-6-Phosphatase/genetics ; Glucose-6-Phosphatase/immunology ; Humans ; Islets of Langerhans/immunology ; Islets of Langerhans/metabolism ; Male ; Pancreas/enzymology ; Pancreas/immunology ; Reverse Transcriptase Polymerase Chain Reaction ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Thymus Gland/enzymology ; Thymus Gland/immunology ; Transcription, Genetic
Chemical Substances	Autoantigens ; Glucose-6-Phosphatase (EC 3.1.3.9) ; G6PC2 protein, human (EC 3.1.3.9.)
Language	English
Publishing date	2013-09-13
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-013-3034-6
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Article ; Online: T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex.

Nature immunology

2015 Volume 16, Issue 11, Page(s) 1153–1161

Abstract: Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally ... ...

Abstract	Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iT(reg)) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iT(reg) TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.
MeSH term(s)	Adaptive Immunity ; Antigen Presentation ; Autoantigens/chemistry ; Autoantigens/genetics ; Autoantigens/metabolism ; Cells, Cultured ; HLA-DR4 Antigen/chemistry ; HLA-DR4 Antigen/genetics ; HLA-DR4 Antigen/metabolism ; Histocompatibility Antigens Class II/chemistry ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/metabolism ; Humans ; Major Histocompatibility Complex/genetics ; Major Histocompatibility Complex/immunology ; Models, Molecular ; Mutagenesis, Site-Directed ; Proinsulin/chemistry ; Proinsulin/genetics ; Proinsulin/immunology ; Protein Interaction Domains and Motifs ; Receptors, Antigen, T-Cell/chemistry ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Autoantigens ; HLA-DR4 Antigen ; Histocompatibility Antigens Class II ; Receptors, Antigen, T-Cell ; Proinsulin (9035-68-1)
Language	English
Publishing date	2015-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/ni.3271
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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