Nonclassical MHC Class II Molecules

Alfonso, Christopher; Karlsson, Lars

doi:10.1146/annurev.immunol.18.1.113

Cited by 138 publications

(124 citation statements)

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“…20 In contrast, non-classical class II genes are not expressed on the cell surface, but form heterotetrameric complexes and enable peptide exchange and loading onto classical class II molecules. 21 This region includes other functionally clustered genes involved in antigen processing including TAP1 and TAP2 (encoding the transporter associated with antigen processing protein), PSMB8 and PSMB9 (involved in ubiquitin-tagged protein degradation) and, in the extended class II region, TAPBP, encoding the TAP-binding protein.…”

Section: Mhc Class II Genes and Their Expressionmentioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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Section: Mhc Class II Genes and Their Expressionmentioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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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“…Once MHC-II-Ii complexes reach lysosome-like Ag processing compartments, Ii is degraded, leaving only a small MHC-II-associated polypeptide (CLIP) bound to the peptide-binding groove (20,21). 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).…”

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confidence: 99%

“…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.…”

mentioning

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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Nonclassical MHC Class II Molecules

Cited by 138 publications

References 171 publications

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

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

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