HLA-DM and the MHC class II antigen presentation pathway

Jensen, Peter E.; Weber, Dominique A.; Thayer, Wesley P.; Chen, Xinjian; Dao, Chin T.

doi:10.1007/bf02790403

Cited by 41 publications

(39 citation statements)

References 67 publications

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“…In the endocytic compartments, DM catalyzes the dissociation of CLIP, facilitating peptide loading onto class II molecules [18][19][20]. Because these events occur within the endocytic compartments, DM molecules should have little role in the presentation of CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide acquired on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…Maturation of class II molecules proceeds as acidic proteases sequentially degrade Ii, releasing the ab dimers [16]. The non-classical HLA, HLA-DM (DM), acts by catalyzing the removal of CLIP and subsequent capture of peptide epitopes by class II molecules [17,18]. The binding of peptide epitopes to class II proteins is selective, whether or not DM is present [18][19][20].…”

mentioning

confidence: 99%

“…The non-classical HLA, HLA-DM (DM), acts by catalyzing the removal of CLIP and subsequent capture of peptide epitopes by class II molecules [17,18]. The binding of peptide epitopes to class II proteins is selective, whether or not DM is present [18][19][20]. The peptides that form stable complexes with class II proteins are displayed at the cell surface for recognition by CD4 + T cells.…”

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confidence: 99%

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HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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Rheumatoid arthritis, an autoimmune disease, is significantly associated with the HLA class II allele HLA-DR4. While the etiology of rheumatoid arthritis remains unknown, type II collagen (CII) is a candidate autoantigen. An immunodominant pathogenic epitope from this autoantigen, CII [261][262][263][264][265][266][267][268][269][270][271][272][273] , which binds to HLA-DR4 and activates CD4 + T cells, has been identified. The non-classical class II antigen, HLA-DM, is also a key component of class II antigen presentation pathways influencing peptide presentation by HLA-DR molecules expressed on professional antigen-presenting cells (APC). Here, we investigated whether the HLA-DR4-restricted presentation of the pathogenic CII 261-273 epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope to activate CD4 + T cells, and that presentation of this peptide is modulated dependent on the level of HLA-DM expression in APC. Mechanistic studies demonstrated that the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide is internalized by APC and edited by HLA-DM molecules in the recycling pathway, inhibiting peptide presentation and T cell recognition. These findings suggest that HLA-DM expression in APC controls class IImediated CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope presentation and regulates CD4 + T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.Key words: CD4 + T cells Á HLA-DM Á HLA-DR Á Peptide presentation Á Type II collagen IntroductionType II collagen (CII) is the major protein component of articular cartilage [1]. It is thought that T and B cell responses to this autoantigen are associated with the development and pathogenesis of rheumatoid arthritis (RA) [2,3]. It is also widely believed that RA is genetically linked to HLA class II molecules, including some HLA-DR4 alleles, and that T cell responses in collagendependent RA are directed towards the immunodominant pathogenic epitope CII [261][262][263][264][265][266][267][268][269][270][271][272][273] [4,5]. Studies also suggest that T cells from patients with RA predominantly recognize the glycosylated form of the immunodominant CII peptide [6,7]. Professional antigen-presenting cells (APC) such as B cells, macrophages and dendritic cells abundantly express HLA class II proteins and play critical roles in the pathogenesis of autoimmune arthritis by presenting autoantigens to T cells [4,5,8].In RA, cartilage proteins including CII undergo degradation by proteases, leading to the generation of peptides that can bind to HLA class II proteins and trigger CD4 + T cell activation [9]. Studies suggest that the peptides are loaded onto class II proteins Eur. J. Immunol. 2008. 38: 1961-1970 Immunomodulation in the endosomal and lysosomal compartments of APC prior to transit to the cell surface for T cell recognition [5...

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Section: Discussionmentioning

confidence: 99%

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HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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“…The CLIP peptide is eventually removed by the peptide editor HLA-DM, whose activity can be regulated by the accessory molecule HLA-DO (22). HLA-DM-mediated removal of CLIP (or other weakly bound peptides) selects for high-affinity epitopes, with the result being that MHC-II on a given APC express thousands of distinct peptides bound to MHC-II (22,23). It is these pMHC-II that are believed to bind to tetraspanins; however, whether the initial association of MHC-II with tetraspanins occurs inside the lysosomal Ag-processing compartment or only after their arrival on the plasma membrane remains to be established.…”

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confidence: 99%

CDw78 Defines MHC Class II-Peptide Complexes That Require Ii Chain-Dependent Lysosomal Trafficking, Not Localization to a Specific Tetraspanin Membrane Microdomain

Poloso

Denzin

Roche

2006

The Journal of Immunology

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MHC class II molecules (MHC-II) associate with detergent-resistant membrane microdomains, termed lipid rafts, which affects the function of these molecules during Ag presentation to CD4+ T cells. Recently, it has been proposed that MHC-II also associates with another type of membrane microdomain, termed tetraspan microdomains. These microdomains are defined by association of molecules to a family of proteins that contain four-transmembrane regions, called tetraspanins. It has been suggested that MHC-II associated with tetraspanins are selectively identified by a mAb to a MHC-II determinant, CDw78. In this report, we have re-examined this issue of CDw78 expression and MHC-II-association with tetraspanins in human dendritic cells, a variety of human B cell lines, and MHC-II-expressing HeLa cells. We find no correlation between the expression of CDw78 and the expression of tetraspanins CD81, CD82, CD53, CD9, and CD37. Furthermore, we find that the relative amount of tetraspanins bound to CDw78-reactive MHC-II is indistinguishable from the amount bound to peptide-loaded MHC-II. We found that expression of CDw78 required coexpression of MHC-II together with its chaperone Ii chain. In addition, analysis of a panel of MHC-II-expressing B cell lines revealed that different alleles of HLA-DR express different amounts of CDw78 reactivity. We conclude that CDw78 defines a conformation of MHC-II bound to peptides that are acquired through trafficking to lysosomal Ag-processing compartments and not MHC-II-associated with tetraspanins.

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“…H uman histocompatibility leukocyte Ag-DM plays a critical role in the MHC class II Ag presentation pathway through its function in catalyzing peptide loading of class II molecules (1). Class II ␣␤ heterodimers initially assemble with the chaperone protein, invariant chain (Ii), 3 in the endoplasmic reticulum of APCs.…”

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Transmembrane Domain-Mediated Colocalization of HLA-DM and HLA-DR Is Required for Optimal HLA-DM Catalytic Activity

Weber

Dao

Jun

et al. 2001

The Journal of Immunology

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HLA-DM catalyzes peptide loading and exchange reactions by MHC class II molecules. Soluble recombinant DM, lacking transmembrane and cytoplasmic domains, was observed to have 200- to 400-fold less activity compared with the full-length protein in assays measuring DM-catalyzed peptide dissociation from purified HLA-DR1 in detergent solutions. Additional studies with truncated soluble DR1 demonstrated that transmembrane domains in DR1 molecules are also required for optimal activity. The potential requirement for specific interaction between the transmembrane domains of DM and DR was ruled out in experiments with chimeric DR1 molecules containing transmembrane domains from either DM or the unrelated protein CD80. These results suggested that the major role of the transmembrane domains is to facilitate colocalization of DM and DR in detergent micelles. The latter conclusion was further supported by the observation that HLA-DM-catalyzed peptide binding to certain murine class II proteins is increased by reducing the volume of detergent micelles. The importance of membrane colocalization was directly demonstrated in experiments in which DM and DR were reconstituted separately or together into membrane bilayers in unilamellar liposomes. Our findings demonstrate the importance of membrane anchoring in DM activity and underscore the potential importance of membrane localization in regulating peptide exchange by class II molecules.

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HLA-DM and the MHC class II antigen presentation pathway

Cited by 41 publications

References 67 publications

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

CDw78 Defines MHC Class II-Peptide Complexes That Require Ii Chain-Dependent Lysosomal Trafficking, Not Localization to a Specific Tetraspanin Membrane Microdomain

Transmembrane Domain-Mediated Colocalization of HLA-DM and HLA-DR Is Required for Optimal HLA-DM Catalytic Activity

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