Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Rapid CLIP Dissociation from MHC II Promotes an Unusual Antigen Presentation Pathway in Autoimmunity

ABSTRACT: A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain-derived class II-associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-Ag7 even in the absence of DM, and this property is related to the type 1 diabetes-associated b57 polymorphism. We generated knock-in Non-obese Diabetic (NOD) mice with a single amino acid change in the CLIP segment of invariant chain in order to moderately slow CLIP dissociation from I-Ag7. These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within b cell secretory granules. Rapid CLIP dissociation enhanced presentation of such extracellular peptides, thus bypassing the conventional MHC class II antigen processing pathway. Autoimmunity-associated MHC class II polymorphisms therefore not only modify binding of self-peptides, but also alter the biochemistry of peptide acquisition.

ORGANISM(S): Mus musculus

PROVIDER: GSE118322 | GEO | 2018/08/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Neoself-antigens are the primary target for autoreactive T cells in human lupus

Project description:Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE.

2024-08-13 | GSE214855 | GEO

Neoself-antigens are the primary target for autoreactive T cells in human lupus

2024-08-13 | GSE265793 | GEO

Rapid CLIP Dissociation from MHC II Promotes an Unusual Antigen Presentation Pathway in Autoimmunity

Project description:Rapid CLIP Dissociation from MHC II Promotes an Unusual Antigen Presentation Pathway in Autoimmunity

| PRJNA485179 | ENA

Cdc42 controls DC-maturation - Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells

Project description:Cell division cycle 42 (Cdc42) is a member of the Rho GTPase family and has pivotal functions in actin organization, cell migration and proliferation. Cdc42 has been shown to regulate antigen (Ag)-uptake in immature dendritic cells (DC) and controls their migration from tissues to lymph nodes. Previous reports demonstrated that Cdc42 is inactivated upon DC-maturation to avoid continued Ag-acquisition. To further study the molecular mechanisms of DC-control by Cdc42, we used bone marrow-derived DCs from Cdc42-deficient mice. We show that Cdc42-deficient DCs are phenotypically mature without additional maturation stimuli, as they upregulate CD86 from intracellular storages to the cell surface. They also accumulate invariant chain (Ii)-MHC class II complexes at the cell surface, which cannot efficiently present peptide Ag for priming of Ag-specific CD4 T cells. Lack of Cdc42 in immature DCs does not allow MHC class II maturation, as lysosomal Cathepsins are lost into the supernatant and Ii-MHC class II complexes cannot mature. Therefore Cdc42-deficient DCs are "pseudomature" and lose most functional hallmarks of antigen-presenting cells. Our results propose that Cdc42 keeps DCs in an immature state, while downregulation of Cdc42-activity during maturation facilitates generation of CD86+MHCII+ mature DCs.

2015-10-12 | PXD001934 | Pride

DNA sequencing for multiple rounds of the pMHC-yeast display selection for 2W, Yae and Fat TCR

Project description:A peptide library was displayed on Ab MHC class II allele expressed on yeast. TCRs of interest were used to select and enrich for cognate peptide-MHC.

2020-06-15 | GSE151070 | GEO

Identification of antigens presented by MHC for vaccines against tuberculosis

Project description:The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. We have purified MHC class-I and MHC-II peptides and analysed them by mass spectrometry. We have successfully identified 97 mycobacterial peptides presented by MHC-II and 54 presented by MHC-I, from 76 and 41 antigens, respectively. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cells from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying novel candidate antigens.

2020-01-08 | E-MTAB-8057 | biostudies-arrayexpress

Loss of B cell Tolerance is TCR Dependent [amplicon-seq]

Project description:We tested orphan TCR autoreactivity using the peptide MHC-TCR chimeric receptor (MCR) co-culture system. In this system, cognate antigen recognition leads to TCR specific NFAT activation in MCR reporter cells expressing a mouse I-Ab MHC class II extracellular domain covalently linked to candidate peptides and an intracellular TCR signaling domain. We used mixed autoimmune bone marrow chimera spleens and kidneys as sources of cDNA to generate a transcriptome-wide library of natural autoantigen peptides . We cloned this cDNA-derived peptide (CDP) autoantigen library into the MCR retroviral backbone and transduced NFAT reporter cells to make a murine autoantigen MCR reporter library (MCR-Lib). We then used this library to screen orphan TCRs identified by scTCR-seq for autoreactivity.

2023-12-29 | GSE229921 | GEO

Gene profilling of splenic CD4+ T cells from naïve H2-O Wildtype and H2-O Knockout mice

Project description:Loss of the MHC Class II accessory molecule H2-O has been shown to alter the peptide repertoir presented by MHC Class II molecules. Using scRNA-Seq we interrogated what outcomes altered antigen presentation was having on the naïve CD4 T cell milieu.

2023-12-18 | GSE246253 | GEO

Blood leukocytes recapitulate diabetogenic peptide-MHC-II complexes displayed in the pancreatic islets

Project description:Assessing the self-peptides presented by susceptible major histocompatibility complex (MHC) molecules is crucial for evaluating the pathogenesis and therapeutics of tissue-specific autoimmune diseases. However, direct examination of such MHC-bound peptides displayed in the target organ remains largely impractical. Here, we demonstrate that the blood leukocytes from non-obese diabetic (NOD) mice presented peptide epitopes to autoreactive CD4 T cells. These peptides were bound to the autoimmune class II MHC molecule, I-Ag7, and originated from insulin B-chain and C-peptide. The presentation required a glucose challenge, which stimulated the release of insulin peptides from pancreatic islets. The circulating leukocytes, especially the B cells, promptly captured and presented these peptides. Although canonical intracellular processing of insulin was involved in the presentation, extracellular binding of catabolized insulin products to I-Ag7 gave rise to a unique pathogenic epitope. Administration of monoclonal antibodies recognizing insulin B-chain abolished the presentation and diminished diabetes incidence. Mass spectrometry analysis of the leukocyte MHC-II peptidomes revealed a series of beta cell derived peptides, with identical sequences to those previously in the islet MHC-II peptidome. Thus, the WBC peptidome echoes that found in islets and serves to identify immunogenic peptides in an otherwise inaccessible tissue.

2021-03-26 | PXD024400 | Pride

A comprehensive mutational scan of the TAPBPR scoop loop defines a region of the sequence-activity landscape for class I MHC interactions

Project description:The loading of high affinity peptides onto nascent class I MHC (MHC-I) molecules is facilitated by chaperones, including the class I-specific chaperone TAP-binding protein-related (TAPBPR). TAPBPR features a ‘scoop’ loop that projects towards the empty MHC-I peptide binding groove and rests above the F pocket. The scoop loop is not found in the closely related homologue tapasin, and therefore may be partly responsible for the unique antigen editing properties of TAPBPR. A deep mutational scan of the TAPBPR scoop loop defines the relative effects of all single amino acid mutations on binding and peptide-mediated release of the murine H2-Dd MHC-I allomorph. Increased hydrophobic packing between the scoop loop and rim of the peptide binding groove tightens the TAPBPR-MHC-I interaction.

2019-10-31 | GSE118568 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data