Assembly and intracellular transport of HLA-DM and correction of the class II antigen-processing defect in T2 cells

Denzin, Lisa K.; Robbins, Ninette F.; Carboy-Newcomb, Cerinda; Cresswell, Peter

doi:10.1016/1074-7613(94)90049-3

Cited by 242 publications

(195 citation statements)

References 41 publications

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“…The first assay used the CerCLIP Ab in a flow cytometric assay to determine the amount of CLIP associated with HLA-DQ on the cell surface of the BLS-1 DQ0604 mutant cell lines. CerCLIP is a mouse mAb produced against CLIP (81-104) (24) and recognizes an epitope on CLIP between amino acids 81 and 92 (R. Ettinger, G. Nepom, and W. Kwok, unpublished data). The second assay examined the binding of CLIP to HLA-DQ in a whole-cell peptide binding assay and determined how well the DQ0604 mutants could bind CLIP.…”

Section: Discussionmentioning

confidence: 99%

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β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

Ettinger

Liu

Nepom

et al. 2000

The Journal of Immunology

103

160

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Studies of the stability of HLA-DQ have revealed a correlation between SDS stability of MHC class II αβ dimers and insulin-dependent diabetes mellitus (IDDM) susceptibility. The MHC class II αβ dimer encoded by HLA-DQA1*0102/DQB1*0602 (DQ0602), which is a dominant protective allele in IDDM, exhibits the greatest SDS stability among HLA-DQ molecules in EBV-transformed B-lymphoblastoid cells and PBLs. DQ0602 is also uniquely SDS stable in the HLA-DM-deficient cell line, BLS-1. We addressed the molecular mechanism of the stability of DQ0602 in BLS-1. A panel of mutants based on the polymorphic differences between HLA-DQA1*0102/DQB1*0602 and HLA-DQA1*0102/DQB1*0604 were generated and expressed in BLS-1. An Asp at β57 was found to be critical for SDS stability, whereas Tyr at β30, Gly at β70, and Ala at β86 played secondary roles. Furthermore, the level of class II-associated invariant chain peptide bound to HLA-DQ did not correlate with SDS stability, suggesting that class II-associated invariant chain peptide does not play a direct role in the unique SDS stability of DQ0602. These results support a role for DQB1 codon 57 in HLA-DQ αβ dimer stability and IDDM susceptibility.

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Section: Discussionmentioning

confidence: 99%

“…Purified CerCLIP (IgG1) was purchased from PharMingen (San Diego, CA). CerCLIP reacts with CLIP bound to HLA class II molecules (24).…”

Section: Cellsmentioning

confidence: 99%

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

Ettinger

Liu

Nepom

et al. 2000

The Journal of Immunology

103

160

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“…cDNA clones for wild-type HLA-DMA and the mutant version of HLA-DMB were cloned into the pMCFR expression vector (21). The vectors were transfected by electro- poration into the B cell line CH27 (22).…”

Section: Methodsmentioning

confidence: 99%

Coevolution of TCR-MHC interactions: Conserved MHC tertiary structure is not sufficient for interactions with the TCR

Kim

Guo

Sant’Angelo

2005

Proc. Natl. Acad. Sci. U.S.A.

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The specificity for self-MHC that is necessary for T cell function is a consequence of intrathymic selection during which T cell antigen receptors (TCRs) expressed by immature thymocytes are tested for their affinity for self-peptide:self-MHC. The germ-line-encoded segments of the TCR, however, are believed to have an innate specificity for structural features of MHC molecules. We directly tested this hypothesis by generating a transgenic mouse system in which the protein HLA-DM is expressed at the surface of thymic cortical epithelial cells in the absence of classical MHC molecules. The specialized intracellular function of HLA-DM has removed this MHC class II-like protein from the evolutionary forces that have been hypothesized to shape TCR-MHC interactions. Our study shows that a structural mimic of MHC class II is not sufficient to appropriately interact with the TCRs expressed by developing thymocytes. This result emphasizes the unique complementarity of TCR-MHC interactions that are maintained by the evolutionary pressures dictated by positive selection.T cell receptor ͉ thymocytes ͉ mice ͉ T lymphocytes ͉ thymus D evelopment of thymocytes is a multistep process that shapes the repertoire of mature T cells. Ideally, the mature T cell antigen receptor (TCR) repertoire is depleted of specificities that are overtly self-reactive, but is also diversified enough to mount effective immune responses (1, 2). Selection is based on the interactions of the TCRs expressed by immature CD4 ϩ CD8 ϩ , double-positive (DP) thymocytes with selfpeptide:self-MHC expressed on the surface of thymic stromal cells. Poorly defined criteria determine whether this receptorligand interaction is of sufficient avidity to drive development of DP thymocytes to mature single-positive, MHC class I-or MHC class II-restricted T cells.Unresolved issues regarding the positive selection of T cells include the extent that specific interactions of the TCR with MHC-bound self-peptides rather than interactions with MHC itself shape the mature CD4 ϩ T cell repertoire. This question has been addressed by a number of systems that have not produced concordant results (3-7). Such contradictory data have led to speculation that different TCRs may have different requirements for recognition of MHC-bound self-peptide. The inherent MHC reactivity of the preselection TCR repertoire is a second issue that has not been definitively answered. In other words, it is not clear whether the germ line-encoded regions of the TCR are predisposed toward interactions with MHC, or, alternatively, whether the ability of TCRs expressed by mature T cells to interact with MHC is fully a consequence of positive selection.Mutagenesis studies have suggested that the TCR has a conserved orientation of interaction with MHC molecules, and, therefore, conserved interactions between MHC molecules and TCRs seemed likely. Crystallographic studies of TCRs bound to MHC, however, have not fully confirmed this prediction (7). In retrospect, perhaps this finding is not surprising, consideri...

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“…The T2 transfectants T2.DR4, T2.DR4.DM, T2.DR11, and T2DR11.DM have been described previously (27). T2.DR1, T2.DR3, and T2.DR3.DM were gifts from Dr. P. Cresswell (Yale University, New Haven, CT).…”

Section: Cell Lines and Plasmidsmentioning

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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Assembly and intracellular transport of HLA-DM and correction of the class II antigen-processing defect in T2 cells

Cited by 242 publications

References 41 publications

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

Coevolution of TCR-MHC interactions: Conserved MHC tertiary structure is not sufficient for interactions with the TCR

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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Assembly and intracellular transport of HLA-DM and correction of the class II antigen-processing defect in T2 cells

Cited by 242 publications

References 41 publications

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA1*0102/DQB1*0602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA1*0102/DQB1*0602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

Coevolution of TCR-MHC interactions: Conserved MHC tertiary structure is not sufficient for interactions with the TCR

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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β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus