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

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          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.

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          Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide.

          L J Stern, J. Brown, T Jardetzky … (1994)
          An influenza virus peptide binds to HLA-DR1 in an extended conformation with a pronounced twist. Thirty-five per cent of the peptide surface is accessible to solvent and potentially available for interaction with the antigen receptor on T cells. Pockets in the peptide-binding site accommodate five of the thirteen side chains of the bound peptide, and explain the peptide specificity of HLA-DR1. Twelve hydrogen bonds between conserved HLA-DR1 residues and the main chain of the peptide provide a universal mode of peptide binding, distinct from the strategy used by class I histocompatibility proteins.
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            Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection.

            Kai Wucherpfennig, Monika-Sarah Schulze, D Sethi … (2012)
            HLA-DR molecules bind microbial peptides in an endosomal compartment and present them on the cell surface for CD4 T cell surveillance. HLA-DM plays a critical role in the endosomal peptide selection process. The structure of the HLA-DM-HLA-DR complex shows major rearrangements of the HLA-DR peptide-binding groove. Flipping of a tryptophan away from the HLA-DR1 P1 pocket enables major conformational changes that position hydrophobic HLA-DR residues into the P1 pocket. These conformational changes accelerate peptide dissociation and stabilize the empty HLA-DR peptide-binding groove. Initially, incoming peptides have access to only part of the HLA-DR groove and need to compete with HLA-DR residues for access to the P2 site and the hydrophobic P1 pocket. This energetic barrier creates a rapid and stringent selection process for the highest-affinity binders. Insertion of peptide residues into the P2 and P1 sites reverses the conformational changes, terminating selection through DM dissociation. Copyright © 2012 Elsevier Inc. All rights reserved.
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              H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection.

              W.David Martin, Geoffrey Hicks, Sanjeev K. Mendiratta … (1996)
              H2-M is a nonconventional major histocompatibility complex (MHC) class II molecule that has been implicated in the loading of peptides onto conventional class II molecules. We generated mice with a targeted mutation in the H2-Ma gene, which encodes a subunit for H2-M. Although the mutant mice express normal class II cell surface levels, these are structurally distinct from the compact SDS-resistant complexes expressed by wild-type cells and are predominantly bound by class II-associated invariant chain peptides (CLIPs). Cells from these animals are unable to present intact protein antigens to class II-restricted T cells and show reduced capacity to present exogenous peptides. Numbers of mature CD4+ T lymphocytes in mutant mice are reduced 3- to 4-fold and exhibit altered reactivities. Overall, this phenotype establishes an important role for H2-M in regulating MHC class II function in vivo and supports the notion that self-peptides contribute to the specificity of T cell positive selection.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Front Immunol
                Journal ID (iso-abbrev): Front Immunol
                Journal ID (publisher-id): Front. Immunol.
                Title: Frontiers in Immunology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-3224
                Publication date (Electronic): 29 August 2013
                Publication date Collection: 2013
                Volume: 4
                Electronic Location Identifier: 260
                Affiliations
                [1] 1Graduate Program in Immunology, Johns Hopkins University , Baltimore, MD, USA
                [2] 2Department of Pathology, Johns Hopkins School of Medicine , Baltimore, MD, USA
                Author notes

                Edited by: Laura Santambrogio, Albert Einstein College of Medicine, USA

                Reviewed by: Edda Fiebiger, Children’s Hospital Boston and Harvard Medical School, USA; Lawrence J. Stern, University of Massachusetts Medical School, USA

                *Correspondence: Scheherazade Sadegh-Nasseri, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building, Room 664C, Baltimore, MD 21205, USA e-mail: ssadegh@ 123456jhmi.edu

                This article was submitted to Antigen Presenting Cell Biology, a section of the journal Frontiers in Immunology.

                Article
                DOI: 10.3389/fimmu.2013.00260
                PMC ID: 3756479
                PubMed ID: 24009612
                SO-VID: fd677ad3-10da-442e-8e18-78728b997a10
                Copyright © Copyright © 2013 Poluektov, Kim and Sadegh-Nasseri.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 31 July 2013
                Date accepted : 15 August 2013
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 58, Pages: 6, Words: 5247
                Categories
                Subject: Immunology
                Subject: Mini Review

                ScienceOpen disciplines: Immunology
                Keywords: hla-do,hla-dr antigens,mhc class ii antigen processing,models for hla-do function,hla-dm
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: hla-do, hla-dr antigens, mhc class ii antigen processing, models for hla-do function, hla-dm

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