Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity.
Yoshinaga ItoOrr AshenbergJason PyrdolAdrienne M LuomaOrit Rozenblatt-RosenMatan HofreeElena ChristianLucas Ferrari de AndradeRong En TayLuc TeytonAviv RegevStephanie K DouganKai W WucherpfennigPublished in: The Journal of experimental medicine (2018)
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 β57 polymorphism. We generated knock-in non-obese diabetic (NOD) mice with a single amino acid change in the CLIP segment of the 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 β cell secretory granules. Rapid CLIP dissociation enhanced the 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.
Keyphrases
- type diabetes
- amino acid
- endoscopic submucosal dissection
- glycemic control
- cardiovascular disease
- adipose tissue
- quantum dots
- insulin resistance
- high fat diet induced
- metabolic syndrome
- weight loss
- genome wide
- stem cells
- gene expression
- highly efficient
- celiac disease
- men who have sex with men
- dna methylation
- hepatitis c virus
- hiv infected