Quality control of MHC class II associated peptides by HLA-DM/H2-M

Vogt, Anne B.; Kropshofer, Harald

doi:10.1006/smim.1999.0197

Cited by 20 publications

(9 citation statements)

References 103 publications

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“…It remains to be elucidated whether under physiological conditions class I molecules regularly enter the TAP-associated complex in the unloaded form, or whether the Tpn:TAP complex predominantly serves as a peptide editor for class I molecules that may enter the complex with prebound peptides of suboptimal affinity. The latter scenario would resemble peptide editing in the HLA-DR/HLA-DM system (63). Taken together, our findings indicate a predominant function of the TAPassociated complex for the loading of HLA class I molecules with peptides conferring optimal stability.…”

Section: Discussionsupporting

confidence: 48%

Recruitment of MHC Class I Molecules by Tapasin into the Transporter Associated with Antigen Processing-Associated Complex Is Essential for Optimal Peptide Loading

Tan

Kropshofer²,

Mandelboim

et al. 2002

The Journal of Immunology

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101

137

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The ER protein tapasin (Tpn) forms a bridge between MHC class I H chain (HC)/β2-microglobulin and the TAP peptide transporter. The function of this TAP-associated complex was unclear because it was reported that soluble Tpn that has lost TAP interaction would be fully competent in terms of peptide loading and Ag presentation. We found, however, that only wild-type human Tpn (hTpn), but not three soluble hTpn variants, a transmembrane domain point mutant of hTpn (L410→F), wild-type mouse Tpn, nor a mouse-human Tpn hybrid, fully up-regulated peptide-dependent Bw4 epitopes when expressed in Tpn-deficient .220.B*4402 cells. Consistent with suboptimal peptide loading, the t1/2 of class I molecules was considerably reduced in the presence of soluble hTpn, hTpn-L410F, and murine Tpn. Furthermore, eluted peptide spectra and the class I-mediated inhibition of NK clones showed distinct differences to the hTpn transfectant. Only wild-type hTpn efficiently recruited HC and calreticulin (Crt) into complexes with TAP and endoplasmic reticulum p57 (ERp57). The L410F mutant was defective in TAP association, but bound to class I molecules, Crt, and ERp57. Mouse Tpn associated with human TAP and ERp57 on the one hand, and with HC and Crt on the other, but failed to recruit normal amounts of HLA class I molecules into the TAP complex. We conclude that the loading with peptides conferring high stability requires the Tpn-mediated introduction of HC into the TAP complex, whereas the mere interaction with Tpn is not sufficient.

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Section: Discussionsupporting

confidence: 48%

Recruitment of MHC Class I Molecules by Tapasin into the Transporter Associated with Antigen Processing-Associated Complex Is Essential for Optimal Peptide Loading

Tan

Kropshofer²,

Mandelboim

et al. 2002

The Journal of Immunology

Self Cite

101

137

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“…Subsequent stepwise degradation of Ii leaves a short peptide fragment, CLIP, to occupy the peptidebinding groove of the emerging class II molecules (5). Before class II complexes appear on the cell surface, most of the CLIP is removed and replaced by other self or Ag peptides through the action of H2-M. H2-M not only promotes the release of CLIP, but also edits the repertoire of presented peptides by catalyzing multiple rounds of peptide exchange to generate thermodynamically stable MHC-II-peptide complexes that are then resistant to subsequent peptide exchange by DM (6)(7)(8). Whereas class II-CLIP is very well characterized as a substrate of DM, studies have suggested that larger Ii intermediates including 21-kDa leupeptin-induced protein can also be converted efficiently to class II-peptide complexes (9).…”

Section: A Ntigens Recognized By Cd4mentioning

confidence: 99%

Immunodeficiency and Autoimmunity in H2-O–Deficient Mice

Jensen

Chen

2013

The Journal of Immunology

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HLA-DO/H2-O is a highly conserved, nonpolymorphic MHC class II-like molecule expressed in association with H2-M in thymic epithelial cells, B lymphocytes, and primary dendritic cells. The physiological function of DO remains unknown. The finding of cell maturation-dependent DO expression in B lymphocytes and dendritic cells suggests the possibility that H2-O functions to promote the presentation of exogenous Ag by attenuating presentation of endogenous self-peptides. In the current study, we report that H2-O−/− mice spontaneously develop high titers of IgG2a/c antinuclear Abs (ANAs) with specificity for dsDNA, ssDNA, and histones. Reconstitution of RAG1−/− mice with T and B cells from H2-O−/− or wild-type mice demonstrated that production of ANAs requires participation of CD4+ T cells from H2-O−/− mice. Bone marrow chimeras demonstrated that loss of H2-O expression in thymic epithelial cells did not induce ANAs, and that lack of H2-O expression in bone marrow-derived cells was sufficient to induce the autoimmune phenotype. Despite production of high titers of autoantibodies, H2-O−/− mice exhibit a delayed generation of humoral immunity to model Ags (OVA and keyhole limpet hemocyanin), affecting all major T-dependent Ig classes, including IgG2a/c. Ag presentation experiments demonstrated that presentation of exogenous Ag by H2-O−/− APC was inefficient as compared with wild-type APC. Thus, H2-O promotes immunity toward exogenous Ags while inhibiting autoimmunity. We suggest that H2-O, through spatially or temporally inhibiting H2-M, may enhance presentation of exogenous Ag by limiting newly generated MHC class II molecules from forming stable complexes with endogenous self-peptides.

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“…It has been generally accepted as a rule that peptides binding to MHC class I molecules are derived from proteins synthesized within the cell, including peptides of genuine cellular origin as well as those encoded by viruses or other intracellular infectious agents. In contrast, MHC class II molecules, in general, bind peptides derived from exogenous proteins that have been processed viaphago‐lysozomes and replace the invariant chain clip fragment associated with class II molecules 1, 2. MHC class I restriction correlates with CD8 + cytotoxic T cells (CTL) and class II restriction with CD4 + T (Th) cells.…”

Section: Introductionmentioning

confidence: 99%