Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity

Yoshinaga Ito, Orr Ashenberg, Jason Pyrdol, Adrienne M. Luoma, Orit Rozenblatt-Rosen, Matan Hofree, Elena Christian, Lucas Ferrari De Andrade, Rong En Tay, Luc Teyton, Aviv Regev, Stephanie K. Dougan*, Kai W. Wucherpfennig*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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 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.

Original languageAmerican English
Pages (from-to)2617-2635
Number of pages19
JournalJournal of Experimental Medicine
Volume215
Issue number10
DOIs
StatePublished - 1 Oct 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 Ito et al.

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