| Autor: |
Ito, Yoshinaga, Ashenberg, Orr, Pyrdol, Jason, Luoma, Adrienne M., Rozenblatt-Rosen, Orit, Hofree, Matan, Christian, Elena, Ferrari de Andrade, Lucas, Tay, Rong En, Teyton, Luc, Regev, Aviv, Dougan, Stephanie K., Wucherpfennig, Kai W. |
| Zdroj: |
The Journal of Experimental Medicine; October 2018, Vol. 215 Issue: 10 p2617-2635, 19p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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