The DMα and DMβ Chain Cooperate in the Oxidation and Folding of HLA-DM

Lith, Marcel van; Benham, Adam M.

doi:10.4049/jimmunol.177.8.5430

Cited by 10 publications

(13 citation statements)

References 56 publications

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“…Cell surface expression of HLA-DR, -DQ, and -DP in the absence of the Ii is consistent with previous observations (23,(25)(26)(27). The result is not likely to be an artifact of overexpression because expression levels were similar to or lower than those found in APCs (20), and the ␤ chain alone did not reach the cell surface. Thus, not only DR, but also DQ and DP interacted physically ( Fig.…”

Section: Is Required For Endosomal-lysosomal Deposition Of Hla-dpsupporting

confidence: 80%

“…2, A-C, ϩTx), similar to that seen in professional APCs. Quantification of repeat experiments showed that of ϳ70 cells counted, 80% (DP), 93% (DR), and 86% (DQ) of ␣␤ϩIiϩDM-expressing cells were positive for the appearance of endosomal-lysosomal structures, as expected from previous experiments with DM (20). DP, DQ, and DR were all able to rescue the known "swollen endosomal-lysosomal vesicle" phenotype that arose when cells expressed Ii alone (supplemental Fig.…”

Section: Is Required For Endosomal-lysosomal Deposition Of Hla-dpmentioning

confidence: 61%

“…Constructs-The DM constructs have been described previously (20). The Ii (short isoform) and DR1 constructs (DRA*0101 and DRB1*010101) were a kind gift of Prof. J. Neefjes (Netherlands Cancer Institute).…”

Section: Methodsmentioning

confidence: 99%

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HLA-DP, HLA-DQ, and HLA-DR Have Different Requirements for Invariant Chain and HLA-DM

Lith

McEwen-Smith

Benham

2010

Journal of Biological Chemistry

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The MHC is central to the adaptive immune response. The human MHC class II is encoded by three different isotypes, HLA-DR, -DQ, and -DP, each being highly polymorphic. In contrast to HLA-DR, the intracellular assembly and trafficking of HLA-DP molecules have not been studied extensively. However, different HLA-DP variants can be either protective or risk factors for infectious diseases (e.g. hepatitis B), immune dysfunction (e.g. berylliosis), and autoimmunity (e.g. myasthenia gravis). Here, we establish a system to analyze the chaperone requirements for HLA-DP and to compare the assembly and trafficking of HLA-DP, -DQ, and -DR directly. Unlike HLA-DR1, HLA-DQ5 and HLA-DP4 can form SDS-stable dimers supported by invariant chain (Ii) in the absence of HLA-DM. Uniquely, HLA-DP also forms dimers in the presence of HLA-DM alone. In model antigen-presenting cells, SDS-stable HLA-DP complexes are resistant to treatments that prevent formation of SDS-stable HLA-DR complexes. The unexpected properties of HLA-DP molecules may help explain why they bind to a more restricted range of peptides than other human MHC class II proteins and frequently present viral peptides.

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Section: Is Required For Endosomal-lysosomal Deposition Of Hla-dpsupporting

confidence: 80%

Section: Is Required For Endosomal-lysosomal Deposition Of Hla-dpmentioning

confidence: 61%

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HLA-DP, HLA-DQ, and HLA-DR Have Different Requirements for Invariant Chain and HLA-DM

Lith

McEwen-Smith

Benham

2010

Journal of Biological Chemistry

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“…Also, the DM may be involved in the oxidation of DO. 37,57 We have tested on DO the reactivity of increasing concentrations of Mags.DO5 and HKC5 in DM + and DM -HEK293T cells (Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a human leucocyte antigen‐DM‐induced structural change in human leucocyte antigen‐DOβ

et al. 2009

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SummaryHuman leucocyte antigen (HLA)-DO is a non-classical major histocompatibility complex class II molecule which modulates the function of HLA-DM and the loading of antigenic peptides on molecules such as HLA-DR. The bulk of HLA-DO associates with HLA-DM and this interaction is critical for HLA-DO egress from the endoplasmic reticulum. HLA-DM assists the early steps of HLA-DO maturation presumably through the stabilization of the interactions between the N-terminal regions of the a and b chains. To evaluate a possible role for HLA-DM in influencing the conformation of HLA-DO, we made use of a monoclonal antibody, Mags.DO5, that was raised against HLA-DO/DM complexes. Using transfected cells expressing mismatched heterodimers between HLA-DR and -DO chains, we found that the epitope for Mags.DO5 is located on the DOb chain and that Mags.DO5 reactivity was increased upon cotransfection with HLA-DM. Our results suggest that HLA-DM influences the folding of HLA-DO in the endoplasmic reticulum. A mutant HLA-DO showing reduced capacity for endoplasmic reticulum egress was better recognized by Mags.DO5 in the presence of HLA-DM. On the other hand, an HLA-DO mutant capable of endoplasmic reticulum egress on its own was efficiently recognized by Mags.DO5, irrespective of the presence of HLA-DM. Taken together, our results suggest that HLA-DM acts as a private chaperone, directly assisting the folding of HLA-DO to promote egress from the endoplasmic reticulum.

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“…After 48 h, cells were washed with PBS, resuspended with Accutase and finally spun down. Cell pellets were washed twice with PBS and lysed as previously described (24).…”

Section: Hla-dm Reconstitution In Hela Cellsmentioning

confidence: 99%

HLA-DMA Polymorphisms Differentially Affect MHC Class II Peptide Loading

Álvaro-Benito

Wieczorek

Sticht

et al. 2015

The Journal of Immunology

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During the adaptive immune response, MHCII proteins display antigenic peptides on the cell surface of APCs for CD4+ T cell surveillance. HLA-DM, a nonclassical MHCII protein, acts as a peptide exchange catalyst for MHCII, editing the peptide repertoire. Although they map to the same gene locus, MHCII proteins exhibit a high degree of polymorphism, whereas only low variability has been observed for HLA-DM. As HLA-DM activity directly favors immunodominant peptide presentation, polymorphisms in HLA-DM (DMA or DMB chain) might well be a contributing risk factor for autoimmunity and immune disorders. Our systematic comparison of DMA*0103/DMB*0101 (DMA-G155A and DMA-R184H) with DMA*0101/DMB*0101 in terms of catalyzed peptide exchange and dissociation, as well as direct interaction with several HLA-DR/peptide complexes, reveals an attenuated catalytic activity of DMA*0103/DMB*0101. The G155A substitution dominates the catalytic behavior of DMA*0103/DMB*0101 by decreasing peptide release velocity. Preloaded peptide–MHCII complexes exhibit ∼2-fold increase in half-life in the presence of DMA*0103/DMB*0101 when compared with DMA*0101/DMB*0101. We show that this effect leads to a greater persistence of autoimmunity-related Ags in the presence of high-affinity competitor peptide. Our study therefore reveals that HLA-DM polymorphic residues have a considerable impact on HLA-DM catalytic activity.

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The DMα and DMβ Chain Cooperate in the Oxidation and Folding of HLA-DM

Cited by 10 publications

References 56 publications

HLA-DP, HLA-DQ, and HLA-DR Have Different Requirements for Invariant Chain and HLA-DM

HLA-DP, HLA-DQ, and HLA-DR Have Different Requirements for Invariant Chain and HLA-DM

Evidence for a human leucocyte antigen‐DM‐induced structural change in human leucocyte antigen‐DOβ

HLA-DMA Polymorphisms Differentially Affect MHC Class II Peptide Loading

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