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

Poluektov, Yuri; Kim, Ae Ryon; Sadegh‐Nasseri, Scheherazade

doi:10.3389/fimmu.2013.00260

Cited by 41 publications

(29 citation statements)

References 57 publications

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“…4A and data not shown). The data on H2-O transcripts drew our attention because DO is known to inhibit the activity of DM, an “editor” needed for dislodging the invariant chain (CD74) derivative, CLIP, and other peptides from the Ag-binding groove of a maturing MHC-II molecule, enabling effective loading of a diverse repertoire of peptides (19, 20). Transcripts encoding both DO chains were expressed at a significantly lower level in perinatal than in adult MECs, independently of Aire (Fig.…”

mentioning

confidence: 99%

Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance

Yang

Fujikado

Kolodin

et al. 2015

Science

381

379

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Aire is an important regulator of immunological tolerance, operating in a minute subset of thymic stromal cells to induce transcripts encoding peptides that guide T-cell selection. Expression of Aire during a perinatal age-window is necessary and sufficient to prevent the multi-organ autoimmunity characteristic of Aire-deficient mice. We report that Aire promotes the perinatal generation of a distinct compartment of Foxp3+CD4+ regulatory T (Treg) cells, which stably persists in adult mice. This population has a role in maintaining self-tolerance, transcriptome and activation profile distinguishable from those of Tregs produced in adults. Underlying the distinct Treg populations are age-dependent, Aire-independent differences in the processing and presentation of thymic stromal-cell peptides, resulting in different T-cell receptor repertoires. Our findings expand the notion of a developmentally layered immune system.

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mentioning

confidence: 99%

Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance

Yang

Fujikado

Kolodin

et al. 2015

Science

381

379

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show abstract

“…Hence, the findings were interpreted as DO competing with DM in interaction with DR leading to the inhibition of DM function. While this model has some support in literature [53], kinetic peptide binding and dissociation experiments performed in the presence of DM and/or DO suggested a different mechanism [51,52]. It was reported that DO reduced binding of DR1 to some peptides, and enhanced the binding of some other peptides to DR1.…”

Section: Role Of Hla-do In Immunodominancementioning

confidence: 78%

“…In addition to DM, another non-classical MHC class II accessory molecule, HLA-DO (H2-O in mice), is known to play a role in peptide exchange [51–53]. Unlike DM, the expression of HLA-DO or H2-O (DO) is restricted to B cells, thymic medulla and certain subsets of DCs, and its cellular trafficking depends on DM.…”

Section: Role Of Hla-do In Immunodominancementioning

confidence: 99%

Determinants of immunodominance for CD4 T cells

Kim¹,

Sadegh‐Nasseri²

2015

Current Opinion in Immunology

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The term immunodominance was originally defined as a restricted T cell response to a short peptide sequence derived from a given protein [1]. The question of what determines immunodominance has been a longstanding battle for the past two decades. Hundreds of papers have been written on different aspects of epitope selection during antigen processing documenting the complexity of the process. Antigen processing machinery involves several accessory molecules and chaperons coevolved with proteins of Major Histocompatibility Complex (MHC) molecules that each plays its part in epitope selection. These molecules are targeted to specialized vesicular compartments that also accommodate antigen processing enzymes called cathepsins. Within the antigen processing compartments, highly regulated pH gradient and reducing conditions and enzymes necessary for denaturation of the antigens are available and function to optimize processing of antigen and selection of the fittest for transport to the cell membrane and presentation to T cells. Despite the complexity, a cell free reductionist antigen processing system was recently reported that included only few purified proteins, but was shown to process and select physiologically relevant epitopes from full length protein antigens [2]. Because of its minimalist nature the system has been quite helpful in dissecting the factors that contribute to epitope selection during antigen processing. In this review, we would summarize and highlight models that may explain how the dominant epitope may be selected for presentation to CD4+ helper T cells.

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“…In Fig 7, the high association of MHC class II antigen presentation , represented by the class II genes including HLA-DM and HLA-DO , reflects the general dominance of HLA-DQ and HLA-DR loci in Fig 2: MHC class II molecules assembled in the ER with the invariant chain (Ii), initially occupying the peptide binding domain, moves into an endosomal compartment and Ii is exchanged with antigenic peptides with the help of HLA-DM and HLA-DO, which down-regulates HLA-DM in B cells [31, 36, 46]. The peptide-MHC class II complex is then displayed on the plasma membrane (Fig 4C).…”

Section: Resultsmentioning

confidence: 99%

Collective Genetic Interaction Effects and the Role of Antigen-Presenting Cells in Autoimmune Diseases

Woo

Reifman

2017

PLoS ONE

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Autoimmune diseases occur when immune cells fail to develop or lose their tolerance toward self and destroy body’s own tissues. Both insufficient negative selection of self-reactive T cells and impaired development of regulatory T cells preventing effector cell activation are believed to contribute to autoimmunity. Genetic predispositions center around the major histocompatibility complex (MHC) class II loci involved in antigen presentation, the key determinant of CD4+ T cell activation. Recent studies suggested that variants in the MHC region also exhibit significant non-additive interaction effects. However, collective interactions involving large numbers of single nucleotide polymorphisms (SNPs) contributing to such effects are yet to be characterized. In addition, relatively little is known about the cell-type-specificity of such interactions in the context of cellular pathways. Here, we analyzed type 1 diabetes (T1D) and rheumatoid arthritis (RA) genome-wide association data sets via large-scale, high-performance computations and inferred collective interaction effects involving MHC SNPs using the discrete discriminant analysis. Despite considerable differences in the details of SNP interactions in T1D and RA data, the enrichment pattern of interacting pairs in reference epigenomes was remarkably similar: statistically significant interactions were epigenetically active in cell-type combinations connecting B cells to T cells and intestinal epithelial cells, with both helper and regulatory T cells showing strong disease-associated interactions with B cells. Our results provide direct genetic evidence pointing to the important roles B cells play as antigen-presenting cells toward CD4+ T cells in the context of central and peripheral tolerance. In addition, they are consistent with recent experimental studies suggesting that the repertoire of B cell-specific self-antigens in the thymus are critical to the effective control of corresponding autoimmune activation in peripheral tissues.

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

Cited by 41 publications

References 57 publications

Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance

Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance

Determinants of immunodominance for CD4 T cells

Collective Genetic Interaction Effects and the Role of Antigen-Presenting Cells in Autoimmune Diseases

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