HLA-DP84Gly constitutively presents endogenous peptides generated by the class I antigen processing pathway

Yuki Yamashita,Ankit Sinha,Munehide Nakatsugawa,Makito Tanaka,Mark D Minden,Marcus O Butler,Yuki Kagoya,Kenji Chamoto,Toshiki Ochi,Tingxi Guo,Thomas Kislinger,Kayoko Saso,Mark Anczurowski,Naoto Hirano

doi:10.1038/ncomms15244

Abstract

Classical antigen processing leads to the presentation of antigenic peptides derived from endogenous and exogenous sources for MHC class I and class II molecules, respectively. Here we show that, unlike other class II molecules, prevalent HLA-DP molecules with β-chains encoding Gly84 (DP84Gly) constitutively present endogenous peptides. DP84Gly does not bind invariant chain (Ii) via the class II-associated invariant chain peptide (CLIP) region, nor does it present CLIP. However, Ii does facilitate the transport of DP84Gly from the endoplasmic reticulum (ER) to the endosomal/lysosomal pathway by transiently binding DP84Gly via a non-CLIP region(s) in a pH-sensitive manner. Accordingly, like class I, DP84Gly constitutively presents endogenous peptides processed by the proteasome and transported to the ER by the transporter associated with antigen processing (TAP). Therefore, DP84Gly, found only in common chimpanzees and humans, uniquely uses both class I and II antigen-processing pathways to present peptides derived from intracellular and extracellular sources.

Highlights

Classical antigen processing leads to the presentation of antigenic peptides derived from endogenous and exogenous sources for major histocompatibility complex (MHC) class I and class II molecules, respectively
Intracellular proteins are processed by the proteasome into peptides, which are transported by the transporterassociated with antigen processing (TAP) into the endoplasmic reticulum (ER), where they associate with MHC class I molecules[2]
Despite the lack of CLIPmediated binding between DP4 and invariant chain (Ii), the forced co-expression of Ii facilitated the transport of both DP4 and DP5 from the ER to the early endosomes/lysosomes, as neither DP4 nor DP5 localized in the ER in the presence of Ii (Fig. 4b). These results demonstrate that irrespective of the sequences at positions 84–87, Ii promotes the transport of DP from the ER to the early endosomes/lysosomes. These results suggest that the class II-associated Ii peptide (CLIP) region is not required for Ii to facilitate the egress of DP from the ER, since DP4 cannot make a nonamer with Ii via the CLIP region as described above

Summary

Introduction

Classical antigen processing leads to the presentation of antigenic peptides derived from endogenous and exogenous sources for MHC class I and class II molecules, respectively. Newly synthesized MHC class II-ab heterodimers associate rapidly with a trimeric form of invariant chain (Ii) in the ER to form a nonamer[3,4] This interaction prevents the premature loading of endogenous peptides on the MHC class II cleft and, by masking the ER retention motif of Ii, facilitates the transport of class II molecules from the ER, through the Golgi, and into endosomal compartments[5]. CLIP is released by the action of H2-DM in mice or human leukocyte antigen-DM (HLA-DM) in humans, which later catalyses the binding of high-affinity peptides found in endosomal compartments[7] These stabilized peptide/class II complexes are exported to the cell surface for presentation to CD4 þ T cells. Molecular and genetic studies of HLA class II molecules have implicated amino-acid polymorphisms, especially those located at the class II peptide-binding cleft, with susceptibility to various diseases. Unlike other class II molecules, DP84Gly, which is only found in common chimpanzees as well as archaic and modern humans, uniquely exploits both class I and II antigen pathways to present both intracellular and extracellular peptides

Methods

Results

Conclusion