HLA-DO as the Optimizer of Epitope Selection for MHC Class II Antigen Presentation

Poluektov, Yuri; Kim, Ae Ryon; Hartman, Isamu Z.; Sadegh‐Nasseri, Scheherazade

doi:10.1371/journal.pone.0071228

Cited by 38 publications

(33 citation statements)

References 69 publications

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“…Poluektov et al . [137] reported a similar effect, and recently acidic pre-treatment of DM or DM–DO was shown to modulate peptide-exchange activity of DM [138]. However, to date, it is assumed that DO affects antigen presentation of peptides that are bound to MHCII proteins under mildly acidic conditions [135].…”

Section: The Central Role Of Hla-dm In Mhcii Antigen Presentationmentioning

confidence: 94%

Human leukocyte Antigen-DM polymorphisms in autoimmune diseases

Álvaro-Benito¹,

Morrison²,

Wieczorek³

et al. 2016

Open Biol.

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Classical MHC class II (MHCII) proteins present peptides for CD4+ T-cell surveillance and are by far the most prominent risk factor for a number of autoimmune disorders. To date, many studies have shown that this link between particular MHCII alleles and disease depends on the MHCII's particular ability to bind and present certain peptides in specific physiological contexts. However, less attention has been paid to the non-classical MHCII molecule human leucocyte antigen-DM, which catalyses peptide exchange on classical MHCII proteins acting as a peptide editor. DM function impacts the presentation of both antigenic peptides in the periphery and key self-peptides during T-cell development in the thymus. In this way, DM activity directly influences the response to pathogens, as well as mechanisms of self-tolerance acquisition. While decreased DM editing of particular MHCII proteins has been proposed to be related to autoimmune disorders, no experimental evidence for different DM catalytic properties had been reported until recently. Biochemical and structural investigations, together with new animal models of loss of DM activity, have provided an attractive foundation for identifying different catalytic efficiencies for DM allotypes. Here, we revisit the current knowledge of DM function and discuss how DM function may impart autoimmunity at the organism level.

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Section: The Central Role Of Hla-dm In Mhcii Antigen Presentationmentioning

confidence: 94%

Human leukocyte Antigen-DM polymorphisms in autoimmune diseases

Álvaro-Benito¹,

Morrison²,

Wieczorek³

et al. 2016

Open Biol.

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“…Similarly, DO expression is generally required for high expression of class II invariant chain peptides (CLIP) presentation at the cell surface; new work from the Pezeshki et al shows that this increases binding of particular superantigens, SEA and TSST-1 [45]. The finding that HLA-DO is a competitive inhibitor of DM action would appear to indicate that DO acts simply by attenuating DM, and not, for example, by modulating DM specificity [3], although Poluektov et al have proposed an additional role for HLA-DO in direct interaction with MHC-II [46]. …”

Section: Progress In Elucidating the Elusive Role Of Do In Immunitymentioning

confidence: 99%

HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation

Mellins

Stern

2014

Current Opinion in Immunology

105

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Peptide loading of class II MHC molecules in endosomal compartments is regulated by HLA-DM. HLA-DO modulates HLA-DM function, with consequences for the spectrum of MHC-bound epitopes presented at the cell surface for interaction with T cells. Here, we summarize and discuss recent progress in investigating the molecular mechanisms of action of HLA-DM and HLA-DO and in understanding their roles in immune responses. Key findings are the long-awaited structures of HLA-DM in complex with its class II substrate and with HLA-DO, and observation of a novel phenotype - autoimmunity combined with immunodeficiency - in mice lacking HLA-DO. We also highlight several areas where gaps persist in our knowledge about this pair of proteins and their molecular biology and immunobiology.

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“…Another attempt toward understanding the role of DO in peptide selection was recently published (43). In this study authors found differences in how DO affected loading of different peptides onto DR1.…”

Section: Mechanisms Of Hla-do Functionmentioning

confidence: 99%

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

Poluektov¹,

Kim²,

Sadegh‐Nasseri³

2013

Front. Immunol.

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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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HLA-DO as the Optimizer of Epitope Selection for MHC Class II Antigen Presentation

Cited by 38 publications

References 69 publications

Human leukocyte Antigen-DM polymorphisms in autoimmune diseases

Human leukocyte Antigen-DM polymorphisms in autoimmune diseases

HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation

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

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