Mechanisms underlying the lack of endogenous processing and CLIP-mediated binding of the invariant chain by HLA-DP84Gly

Mark Anczurowski, Yuki Yamashita, Munehide Nakatsugawa, Toshiki Ochi, Yuki Kagoya, Tingxi Guo, Chung Hsi Wang, Muhammed A. Rahman, Kayoko Saso, Marcus O. Butler, Naoto Hirano

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

While the principles of classical antigen presentation via MHC class II are well-established, the mechanisms for the many routes of cross-presentation by which endogenous antigens become associated with class II molecules are not fully understood. We have recently demonstrated that the single amino acid polymorphism HLA-DPβ84Gly (DP84Gly) is critical to abrogate class II invariant chain associated peptide (CLIP) region-mediated binding of invariant chain (Ii) to DP, allowing endoplasmic reticulum (ER)-resident endogenous antigens to constitutively associate with DP84Gly such as DP4. In this study, we demonstrate that both the CLIP and N-terminal non-CLIP Ii regions cooperatively generate an Ii conformation that cannot associate with DP84Gly via the CLIP region. We also demonstrate the ability of DP4 to efficiently process and present antigens encoded in place of CLIP in a chimeric Ii, regardless of wild type Ii and HLA-DM expression. These data highlight the complex interplay between DP polymorphisms and the multiple Ii regions that cooperatively regulate this association, ultimately controlling the presentation of endogenous antigens on DP molecules. These results may also offer a mechanistic explanation for recent studies identifying the differential effects between DP84Gly and DP84Asp as clinically relevant in human disease.

Original languageEnglish
Article number4804
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • General

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