HLA-DM mediates peptide exchange by interacting transiently and repeatedly with HLA-DR1

Narayan, Kedar; Su, Katherine W.; Chou, Chih Ling; Khoruzhenko, Stanislav; Sadegh‐Nasseri, Scheherazade

doi:10.1016/j.molimm.2009.07.001

Cited by 32 publications

(31 citation statements)

References 33 publications

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“…DM binds MHC II near the N-terminus of the peptide binding groove and disrupts peptide binding by inducing or stabilizing a conformation with altered alpha subunit 3 10 helix and adjacent extended strand (21, 28, 36). The region with altered structure is involved in key MHC II-peptide interactions (21, 32, 35). MHC II-peptide complexes appear to be highly dynamic and adopt various conformations (40, 41).…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Role of HLA-DM in MHC Class II–Peptide Association Reactions

Yin

Maben

Becerra

et al. 2015

The Journal of Immunology

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Antigen presentation by major histocompatibility complex class II molecules (MHC II) to CD4+ T cells plays a key role in the regulation of the adaptive immune response. Loading of antigenic peptides onto MHC II is catalyzed by HLA-DM (DM), a non-classical MHC II molecule. The mechanism of DM-facilitated peptide loading is an outstanding problem in the field of antigen presentation. In this study we systemically explored possible kinetic mechanisms for DM-catalyzed peptide association, by measuring real time peptide association kinetics using fluorescence polarization assays and comparing the experimental data with numerically modeled peptide association reactions. We found that DM does not facilitate peptide association by stabilizing peptide-free MHC II against aggregation. Moreover, DM does not promote transition of an inactive peptide-averse conformation of MHC II to an active peptide-receptive conformation. Instead, DM forms an intermediate with MHC II that binds peptide with faster kinetics than MHC II in the absence of DM. In the absence of peptides, interaction of MHC II with DM leads to inactivation and formation of a peptide-averse form. This study provides novel insights into how DM efficiently catalyzes peptide loading during antigen presentation.

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Section: Introductionmentioning

confidence: 99%

Evaluating the Role of HLA-DM in MHC Class II–Peptide Association Reactions

Yin

Maben

Becerra

et al. 2015

The Journal of Immunology

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“…The strong interactions within and between HLA-DQ and DR loci in B cells (Fig 6A) are consistent with this core component (antigen-presentation in thymic APCs) of T1D phenotype, and supports our earlier conclusion that thymic B cells are among the major components of the APC repertoire. The HLA-DM gene encodes a chaperone that facilitates the loading of peptides in the late endosome within this antigen presentation pathway [31, 36] (Fig 4C); hence, the interaction of the DM-proximal region with HLA-DQ and DR .…”

Section: Resultsmentioning

confidence: 99%

“…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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“…To generate peptides with increased DM-susceptibility, we substituted the P1 pocket residue of A2 104–117 from tryptophan to isoleucine (W1I) or to threonine (W1T), because the P1 pocket residue is one of the major anchor residues (Murthy and Stern, 1997; Stern et al, 1994) and has been implicated in determining DM-susceptibility (Anders et al, 2011; Narayan et al, 2009; Pos et al, 2012; Schulze and Wucherpfennig, 2012; Yin and Stern, 2013). As expected, A2 104–117 , W1I and W1T all showed a concentration-dependent inhibition on the binding of probe peptide Alexa488-HA 306–318 to DR1, with A2 104–117 having the highest affinity and W1T the lowest (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, it has been demonstrated that MHCII molecules undergo a reversible isomerization between peptide-receptive and peptide-averse states, and DM may catalyze peptide association by accelerating the transition of peptide-averse to peptide-receptive conformation, or stabilizing the peptide-receptive form (Grotenbreg et al, 2007; Natarajan et al, 1999; Rabinowitz et al, 1998). Moreover, multiple intermediates formed between peptide, MHCII and DM during peptide association, dissociation and exchange have been proposed although the detailed mechanisms are still in debate (Anders et al, 2011; Ferrante et al, 2008; Grotenbreg et al, 2007; Narayan et al, 2009; Pashine et al, 2003; Pos et al, 2012; Zarutskie et al, 2001). It is possible that reaction steps not included in our simulation reaction scheme might put some constraints on the interpretation on the IC 50 data.…”

Section: Discussionmentioning

confidence: 99%

A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC50 determination

Yin

Stern

2014

Journal of Immunological Methods

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HLA-DM (DM) functions as a peptide editor that mediates the exchange of peptides loaded onto MHCII molecules by accelerating peptide dissociation and association kinetics. The relative DM-susceptibility of peptides bound to MHCII molecules correlates with antigen presentation and immunodominance hierarchy, and measurement of DM-susceptibility has been a key effort in this field. Current assays of DM-susceptibility, based on differential peptide dissociation rates measured for individually labeled peptides over a long time base, are difficult and cumbersome. Here, we present a novel method to measure DM-susceptibility based on peptide binding competition assays performed in the presence and absence of DM, reported as a delta-IC50 (change in 50% inhibition concentration) value. We simulated binding competition reactions of peptides with various intrinsic and DM-catalyzed kinetic parameters and found that under a wide range of conditions the delta-IC50 value is highly correlated with DM-susceptibility as measured in off-rate assay. We confirmed experimentally that DM-susceptibility measured by delta-IC50 is comparable to that measured by traditional off-rate assay for peptides with known DM-susceptibility hierarchy. The major advantage of this method is that it allows simple, fast and high throughput measurement of DM-susceptibility for a large set of unlabeled peptides in studies of the mechanism of DM action and for identification of CD4+ T cell epitopes.

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HLA-DM mediates peptide exchange by interacting transiently and repeatedly with HLA-DR1

Cited by 32 publications

References 33 publications

Evaluating the Role of HLA-DM in MHC Class II–Peptide Association Reactions

Evaluating the Role of HLA-DM in MHC Class II–Peptide Association Reactions

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

A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC50 determination

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