HLA-DO and Its Role in MHC Class II Antigen Presentation

Abstract

Helper T cells are stimulated to fight infections or diseases upon recognition of peptides from antigens that are processed and presented by the proteins of Major Histocompatibility Complex (MHC) Class II molecules. Degradation of a full protein into small peptide fragments is a lengthy process consisting of many steps and chaperones. Malfunctions during any step of antigen processing could lead to the development of self-reactive T cells or defective immune response to pathogens. Although much has been accomplished regarding how antigens are processed and presented to T cells, many questions still remain unanswered, preventing the design of therapeutics for direct intervention with antigen processing. Here, we review published work on the discovery and function of a MHC class II molecular chaperone, HLA-DO, in human, and its mouse analog H2-O, herein called DO. While DO was originally discovered decades ago, elucidating its function has proven challenging. DO was discovered in association with another chaperone HLA-DM (DM) but unlike DM, its distribution is more tissue specific, and its function more subtle.

Keywords: HLA-DM; HLA-DO; HLA-DR antigens; MHC class II antigen processing; models for HLA-DO function.

Figure 1

A model for the effects of HLA-DO on antigen presentation. Starting from a CLIP-bound DM-sensitive conformation (conformation 1), DR interacts with DM (conformation 1’), and a peptide-receptive open conformation is generated (conformation 2). An open conformation can also be induced by DM interacting with empty DR (conformation 6’). DO or DM/DO complexes interact with peptide-receptive DR molecules and stabilize an overly receptive conformation (conformation 3). In the pool of available peptides those that form DM-sensitive complexes with DR do not get a chance to stabilize in the groove. On the contrary, those peptides that form DM-resistant complexes undergo conformational changes and form DR-compact dimers (conformation 4), which are shuttled to the cell membrane (conformation 5). If DR-receptive (conformation 2) does not find a peptide to bind it converts to a closed conformation (conformation 6).