A new human HLA class II-related locus, DM

Kelly, Anita M.; Monaco, John J.; Cho, Sungae; Trowsdale, John

doi:10.1038/353571a0

Cited by 256 publications

(145 citation statements)

References 14 publications

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“…CIITA observed in the SV-40-transfected clone, 3A10, is totally consistent with the results from HTV-59A, and demonstrates that thyrocytes do express the genes important for antigen processing and presentation. The observation that the promoter regions of DMA and DMB are similar to those of the class II genes indicates that DM may also be regulated by CIITA [5]. The DM genes are regulated by a mechanism common to the HLA class II genes, through the conserved X-Y-Z promoter region and the transcription factors CIITA and RFX [29].…”

Section: Discussionmentioning

confidence: 99%

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HLA-DMB expression by thyrocytes: indication of the antigen-processing and possible presenting capability of thyroid cells

Wu¹,

Biro²,

Mirakian³

et al. 1999

Clinical and Experimental Immunology

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SUMMARYExpression of HLA class II molecules on thyrocytes is a characteristic feature of autoimmune thyroid disease and may lead the thyroid cells to present autoantigens to CD4 þ T lymphocytes. Since HLA-DM is a critical molecule in class II-restricted antigen processing and presentation, we assessed the expression of HLA-DMB, -invariant chain (Ii), class II transactivator (CIITA) and DRA in an untransformed, pure thyrocyte strain HTV-59A. Here we report that both HLA-DMB mRNA and the protein are expressed in thyrocytes and that CIITA expression is enhanced by interferon-gamma (IFNg) treatment and occurs before DMB, Ii and DRA up-regulation, suggesting CIITA expression is a requirement for antigen processing in thyrocytes. These results indicate that thyrocytes are capable of antigen processing and possibly antigen presentation to T cells.

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Section: Discussionmentioning

confidence: 99%

“…Two novel genes, HLA-DMA and DMB, have recently been identified and latterly demonstrated to be important for antigen processing and presentation [5][6][7]. Their function is to catalyse the removal of part of the invariant chain (CLIP) from the MHC class II ab-CLIP complex and to facilitate antigenic peptide loading to class II molecules.…”

Section: Introductionmentioning

confidence: 99%

HLA-DMB expression by thyrocytes: indication of the antigen-processing and possible presenting capability of thyroid cells

Wu¹,

Biro²,

Mirakian³

et al. 1999

Clinical and Experimental Immunology

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“…Double-stranded cDNA was then amplified by PCR for 20 cycles, digested with SalI-EcoRI, and cloned in pBluescript KS ϩ (pBS 1-DM␤.1). The complete DNA coding sequence was verified by sequencing, and the predicted amino acids sequence corresponds to the published sequence (52).…”

Section: Dr/do␤cyto and Dr/dm␤cyto Reporter Moleculesmentioning

confidence: 99%

Functional Characterization of a Lysosomal Sorting Motif in the Cytoplasmic Tail of HLA-DOβ

Brunet¹,

Samaan²,

Deshaies³

et al. 2000

Journal of Biological Chemistry

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HLA-DO is an intracellular non-classical class II major histocompatibility complex molecule expressed in the endocytic pathway of B lymphocytes, which regulates the loading of antigenic peptides onto classical class II molecules such as HLA-DR. The activity of HLA-DO is mediated through its interaction with the peptide editor HLA-DM. Here, our results demonstrate that although HLA-DO is absolutely dependent on its association with DM to egress the endoplasmic reticulum, the cytoplasmic portion of its ␤ chain encodes a functional lysosomal sorting signal. By confocal microscopy and flow cytometry analysis, we show that reporter transmembrane molecules fused to the cytoplasmic tail of HLA-DO␤ accumulated in Lamp-1 ؉ vesicles of transfected HeLa cells. Mutagenesis of a leucine-leucine motif abrogated lysosomal accumulation and resulted in cell surface redistribution of reporter molecules. Finally, we show that mutation of the di-leucine sequence in DO␤ did not alter its lysosomal sorting when associated with DM molecules. Taken together, these results demonstrate that lysosomal expression of the DO-DM complex is mediated primarily by the tyrosine-based motif of HLA-DM and suggest that the DO␤-encoded motif is involved in the fine-tuning of the intracellular sorting. Major histocompatibility complex (MHC)1 class II molecules are heterodimeric cell surface glycoproteins that present antigens to CD4 ϩ T cells (1). The antigenic peptide-class II complexes are expressed on specialized antigen-presenting cells such as macrophages and B lymphocytes. Following their synthesis, the ␣ and ␤ subunits of the class II molecule associate in the endoplasmic reticulum (ER) together with the invariant chain (Ii) (2). The latter folds in part through the groove of the class II molecule, stabilizing the ␣␤ heterodimer and preventing the undesirable binding of ER polypeptides (3-6). Studies using mice with inactivated Ii genes suggested that Ii is necessary for efficient exit of newly synthesized class II molecules from the ER (7, 8). However, it was later demonstrated that high levels of class II molecules reach the surface of Ii Ϫ dendritic cells (9). Moreover, transfected cells express a substantial amount of class II molecules at their plasma membrane even in the absence of Ii (10). Such a phenotype probably results from the binding of endogenous peptides or polypeptides present in the ER (6, 11) and supports the notion that occupancy of the peptide-binding groove is sufficient to allow ER egress (12).Another function of Ii is to direct efficiently MHC class II molecules to the endocytic antigen-loading compartments (13-15). Two short leucine-based sequences located in the cytoplasmic tail of Ii are responsible for trafficking through the endocytic pathway (16,17). Similar motifs in many proteins are specifically recognized at the cell surface and trans-Golgi by elements of the sorting machinery (reviewed in Ref. 18).Once the class II-Ii complex reaches the endosomal compartments, the invariant chain is progressively degraded by v...

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“…rIFN-␥ strongly induces the expression of MHC class II molecules and other proteins involved in Ag presentation, like HLA-DM (37,38). This could have an impact on the levels of MHC class II in phagosomes containing mycobacteria.…”

Section: Conversion Of Phagosomes To Miic-like Compartments By Activamentioning

confidence: 99%

Interaction ofMycobacterium avium-Containing Phagosomes with the Antigen Presentation Pathway

Ullrich

Beatty

Russell

2000

The Journal of Immunology

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Pathogenic mycobacteria infect macrophages where they replicate in phagosomes that minimize contact with late endosomal/lysosomal compartments. Loading of Ags to MHC class II molecules occurs in specialized compartments with late endosomal characteristics. This points to a sequestration of mycobacteria-containing phagosomes from the sites where Ags meet MHC class II molecules. Indeed, in resting macrophages MHC class II levels decreased strongly in phagosomes containing M. avium during a 4-day infection. Phagosomal MHC class II of early (4 h) infections was partly surface-derived and associated with peptide. Activation of host macrophages led to the appearance of H2-M, a chaperon of Ag loading, and to a strong increase in MHC class II molecules in phagosomes of acute (1 day) infections. Comparison with the kinetics of MHC class II acquisition by IgG-coated bead-containing phagosomes suggests that the arrest in phagosome maturation by mycobacteria limits the intersection of mycobacteria-containing phagosomes with the intracellular trafficking pathways of Ag-presenting molecules.

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A new human HLA class II-related locus, DM

Cited by 256 publications

References 14 publications

HLA-DMB expression by thyrocytes: indication of the antigen-processing and possible presenting capability of thyroid cells

HLA-DMB expression by thyrocytes: indication of the antigen-processing and possible presenting capability of thyroid cells

Functional Characterization of a Lysosomal Sorting Motif in the Cytoplasmic Tail of HLA-DOβ

Interaction ofMycobacterium avium-Containing Phagosomes with the Antigen Presentation Pathway

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