Version on PubMed Central for supplementary material.AcknowledgmentsThe authors thank Dr. Ivo Vellekoop for many helpful discussions and Dr. Phil Willems for comments on the manuscript. BJ is recipient of a Sir Henry Wellcome Fellowship by the Wellcome Trust. YMW acknowledges support from the National Science Scholarship, awarded by the Agency for Science, Technology and Research, Singapore. This work is supported by NIH 1DP2OD007307-01 and DARPA W31P4Q-11-1-0008.
HLA-DO is a nonclassical MHC molecule that is closely related in sequence and structure to the HLA class II molecules DP, DQ and DR. It shares a similar degree of homology with these classical molecules as they do with each other, suggesting a common ancestry [1]. It also shares conserved promoter elements with MHCII and requires CIITA, the master regulator of class II gene expression, for transcription [2]. However, tissue expression of DO is much more restricted than for MHCII, with DO protein mainly detected in B cells but also reported in thymic epithelium and some DC subsets [3]. HLA-DO is composed of alpha and beta chains that associate directly with HLA-DM early in biosynthesis. This pairing is essential for DO maturation [3, 6]. In the absence of DM, DO dimers fail to assemble properly and locate predominantly to the ER. Consequently, DO is always expressed togetherCorrespondence: Dr. Adrian P. Kelly e-mail: [email protected] HLA-DM and the two molecules co-localise in late endocytic compartments [5, 7]. Experimentally, the dependency of DO for DM can be circumvented by a proline to valine substitution in the membrane distal domain of DO and this mutation provides a useful tool for the study of DO in the absence of DM [6]. Although the genes encoding DO were discovered soon after those for MHCII, its role in class II antigen presentation is not well defined. HLA-DP, -DQ and -DR function to present peptides to CD4-restricted T cells. They assemble in the ER with the chaperone molecule invariant chain (Ii) and traffic to endosomal compartments where Ii is degraded [8]. A small fragment of Ii, CLIP, remains in the peptide-binding groove and is removed through interaction with the nonclassical molecule HLA-DM [9]. The exact role of DO in MHCII antigen presentation remains uncertain but it does not associate directly with peptide. Instead it is proposed to function as a negative regulator of HLA-DM [10]. Direct examination of the interaction of DM and MHCII through crystallography has proven difficult. However, recent cocrystallisation of a DO/DM complex has shed light on the function of both DM and DO [11]. These studies demonstrate that DOC2013 WILEY-VCH Verlag GmbH Co.Atacicept KGaA, Weinheimwww.eji-journal.Sorafenib euMartin Jahnke et al.PMID:23776646 Eur. J. Immunol. 2013. 43: 1153adopts an MHCII-like structure and associates in a side-by-side arrangement with DM. DO binds to the same sites on DM as those predicted to be involved in DM/DR interactions [11]. Mechanistically, DM assists peptide release by disrupting key MHC-peptide interactions and it also stabilises MHCII in a peptide-receptive conformation [12, 13]. In contrast, HLA-DO acts as a competitive inhibitor of DM and may allow “fine-tuning” of peptide loading during the process of affinity maturation [11, 14]. This may be achieved by pH-dependent dissociation of DM/DO complexes thereby allowing “focusing” of peptide loading to late endocytic compartments [3]. DO has also been shown to mediate redistribution of DM and MHCII to th.