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

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 (DP 84Gly ) constitutively present endogenous peptides. DP 84Gly 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 DP 84Gly from the endoplasmic reticulum (ER) to the endosomal/lysosomal pathway by transiently binding DP 84Gly via a non-CLIP region(s) in a pH-sensitive manner. Accordingly, like class I, DP 84Gly constitutively presents endogenous peptides processed by the proteasome and transported to the ER by the transporter associated with antigen processing (TAP). Therefore, DP 84Gly , 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. MHC class I and II molecules generally present endogenous and exogenous peptides, respectively, through distinct mechanisms. Here, the authors show that the class II molecule HLA-DP 84Gly uses both class I and II mechanisms to constitutively present peptides.