Selection of the MHC Class II-associated peptide repertoire by HLA-DM

Arndt, S. O.; Vogt, Anne B.; Hämmerling, Günter J.; Kropshofer, Harald

doi:10.1007/bf02786394

Cited by 11 publications

(10 citation statements)

References 76 publications

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“…Introduction of functional tapasin into these cells restores normal class I expression and functional Ag presentation (7,9,(13)(14)(15)(16). These multiple functions of tapasin have led to speculation that it may be involved in peptide editing of class I bound ligands (10, 16 -21) in a manner similar to that of HLA-DM in class II Ag presentation (22). More recent studies have provided biochemical evidence for a specific peptide-editing function for tapasin (9).…”

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confidence: 99%

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Barnden

Purcell

Gorman³

et al. 2000

The Journal of Immunology

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The murine class I H-2Kb molecule achieves high level surface expression in tapasin-deficient 721.220 human cells. Compared with their behavior in wild-type cells, Kb molecules expressed on 721.220 cells are more receptive to exogenous peptide, undergo more rapid surface decay, and fail to form macromolecular peptide loading complexes. As a result, they are rapidly transported to the cell surface, reflecting a failure of endoplasmic reticulum retention mechanisms in the absence of loading complex formation. Despite the failure of Kb molecules to colocalize to the TAP and their rapid egress to the cell surface, Kb is still capable of presenting TAP-dependent peptides in the absence of tapasin. Furthermore, pool sequencing of peptides eluted from these molecules revealed strict conservation of their canonical H-2Kb-binding motif. There was a reduction in the total recovery of peptides associated with Kb molecules purified from the surface of tapasin-deficient cells. Comparison of the peptides bound to Kb in the presence and absence of tapasin revealed considerable overlap in peptide repertoire. These results indicate that in the absence of an interaction with tapasin, Kb molecules fail to assemble with calreticulin and TAP, yet they are still capable of acquiring a diverse array of peptides. However, a significant proportion of these peptides appear to be suboptimal, resulting in reduced cell surface stability of Kb complexes. Taken together, the findings indicate that tapasin plays an essential role in the formation of the class I loading complex, which retains class I heterodimers in the endoplasmic reticulum until optimal ligand selection is completed.

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confidence: 99%

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Barnden

Purcell

Gorman³

et al. 2000

The Journal of Immunology

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“…Strikingly, these experiments revealed that mice lacking DM expression generated greatly enhanced responses to the HEL 103-117 I-E restricted epitope compared with WT mice (Fig. 6B), despite eliciting similarly low responses to the I-A d restricted HEL (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) peptide. These results suggest that the preimmune T cell repertoire in DM Ϫ/Ϫ mice is enriched for I-E restricted CD4 T cells.…”

Section: Dm-dependent I-e-restricted Peptides Recruit More T Cells Inmentioning

confidence: 92%

“…To accurately assess the immunodominance pattern to the MalE Ag, we established arbitrary exclusion criteria, with responses consistently representing 4% or less of the total response being eliminated from further analysis. Using this criterion, we found that CD4 T cells from WT mice responded to a total of 9 peptide pools (pools 8,11,12,14,15,16,21,26, and 30), including 8, 11, and 26, pools that contain peptides corresponding to previously characterized MalE epitopes (45,46). Interestingly, when responses in DM Ϫ/Ϫ mice were analyzed, a similar number of peptide pools elicited a productive IL-2 response, with a total of 8 (pools 4,7,8,10,11,12,14, and 16) displaying reactivity above 4% of the total response.…”

Section: Identification Of the Immunodominance Pattern To Male Ag Inmentioning

confidence: 99%

“…Using this criterion, we found that CD4 T cells from WT mice responded to a total of 9 peptide pools (pools 8,11,12,14,15,16,21,26, and 30), including 8, 11, and 26, pools that contain peptides corresponding to previously characterized MalE epitopes (45,46). Interestingly, when responses in DM Ϫ/Ϫ mice were analyzed, a similar number of peptide pools elicited a productive IL-2 response, with a total of 8 (pools 4,7,8,10,11,12,14, and 16) displaying reactivity above 4% of the total response. Surprisingly, this analysis revealed that several of the pools recognized in DM Ϫ/Ϫ mice were distinct from those eliciting responses in WT mice, associated with a gain in T cell activation to new peptide pools, including 4, 7, and 10, and the reciprocal reduction or loss of reactivity to pools 8, 11 and 26. This pattern of epitope shift between WT and DM Ϫ/Ϫ T cell responses was further reinforced when individual peptides from pools 8 through 11, as well as 25 and 26 were used to restimulate CD4 T cells in IL-2 ELISPOT assays.…”

Section: Identification Of the Immunodominance Pattern To Male Ag Inmentioning

confidence: 99%

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An MHC Class II Restriction Bias in CD4 T Cell Responses toward I-A Is Altered to I-E in DM-Deficient Mice

Menges

Jenks

Bikoff

et al. 2008

The Journal of Immunology

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The MHC-encoded cofactor DM catalyzes endosomal loading of peptides onto MHC class II molecules. Despite evidence from in vitro experiments that DM acts to selectively edit the repertoire of class II:peptide complexes, the consequence of DM expression in vivo, or a predictive pattern of DM activity in the specificity of CD4 T cell responses has remained unresolved. Therefore, to characterize DM function in vivo we used wild-type (WT) or DM-deficient (DM−/−) mice of the H-2d MHC haplotype and tested the hypothesis that DM promotes narrowing of the repertoire of class II:peptide complexes displayed by APC, leading to a correspondingly selective CD4 T cell response. Surprisingly, our results indicated that DM−/− mice do not exhibit a broadened CD4 T cell response relative to WT mice, but rather shift their immunodominance pattern to new peptides, a pattern associated with a change in class II isotype-restriction. Specifically, we found that CD4 T cell responses in WT mice were primarily restricted to the I-A class II molecule, whereas DM−/− mice recognize peptides in the context of I-E. The observed shift in isotype-restriction appeared to be due in part to a modification in the peripheral CD4 T cell repertoire available for peptide recognition.

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“…li generates CLIP, subsequently released from the MHC class IIbinding grove in a peptide editing process catalyzed by the nonclassical MHC class II molecules HLA-DMA/DMB. 8 HLA-DM acts as a chaperone and protects empty MHC class II complexes until they are able to bind peptides that show sufficient stability to bind to MHC class II molecules. Despite the fact that MHC class II molecules, Ii and HLA-DM are encoded on separated chromosomes, they are partially coregulated by the class II transcriptional activator CIITA.…”

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confidence: 99%

Differential MHC class II component expression in HPV‐positive cervical cancer cells: Implication for immune surveillance

Zehbe¹,

Höhn²,

Pilch³

et al. 2005

Intl Journal of Cancer

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Effective eradication of human papillomavirus (HPV)-positive tumors may require CD81 and CD41 T-cell-mediated immune responses. Ectopic expression of MHC class II surface molecules has been described in the context of cervical cancer, but coexpression with other components of the MHC class II antigen presentation pathway has not been addressed. We have evaluated the MHC class II antigen presentation pathway in malignant squamous epithelium of HPV1 cervical cancer lesions by in situ costaining HLA-DR with CLIP or DMA/DMB. Cervical cancer cells exhibit 3 MHC class II phenotypes: (i) DR1/CLIP1 or DM1; (ii) DR1/CLIP-or DM-; and (iii) DR-/CLIP1 or DM1. The identical profile has been identified in HPV1 ME180 cells, which serve as a target for HLA-DR4-restricted and HPV68, E7-specific CD41 T cells. IFN-c pretreatment of ME180 cells, associated with differential trafficking of MHC class II molecules, is necessary for effective T-cell recognition. Although proinflammatory cytokines may facilitate MHC class II-restricted antigen recognition in tumor cells, different phenotypes of the MHC class II antigen presentation pathway may be associated with evasion from CD41-mediated cellular immune responses. ' 2005 Wiley-Liss, Inc.

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Selection of the MHC Class II-associated peptide repertoire by HLA-DM

Cited by 11 publications

References 76 publications

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

Tapasin-Mediated Retention and Optimization of Peptide Ligands During the Assembly of Class I Molecules

An MHC Class II Restriction Bias in CD4 T Cell Responses toward I-A Is Altered to I-E in DM-Deficient Mice

Differential MHC class II component expression in HPV‐positive cervical cancer cells: Implication for immune surveillance

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