I-Ag7 is subject to post-translational chaperoning by CLIP

Rinderknecht, Cornelia H.; Lü, Ning; Crespo, Oliver; Truong, Phi; Hou, Tieying; Wang, Nan; Rajasekaran, Narendiran; Mellins, Elizabeth

doi:10.1093/intimm/dxq056

Cited by 11 publications

(18 citation statements)

References 46 publications

(81 reference statements)

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“…This may afford opportunities for loading of peptides without participation of the editing function of DM (40), exacerbating promiscuous peptide binding in vivo . The low stability of A g7 /CLIP is partly attributable to the P9 pocket preferences of this allele, because stabilisation can be achieved by replacing Met98 of CLIP (murine Ii numbering) at P9 with a negatively charged residue (44). …”

Section: Type 1 Diabetesmentioning

confidence: 99%

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On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

Busch

Riva

Hadjinicolaou

et al. 2012

Expert Rev. Mol. Med.

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This review discusses mechanisms that link allelic variants of MHC class II molecules (MHCII) to immune pathology. We focus on HLA-DQ (DQ) alleles associated with celiac disease (CD) and type 1 diabetes (T1D) and the role of the murine DQ-like allele, H2-Ag7 (Ag7), in murine T1D. MHCII molecules bind peptides, and alleles vary in their peptide-binding specificity. Disease-associated alleles permit binding of disease-inducing peptides, such as gluten-derived, Glu-/Pro-rich gliadin peptides in CD and peptides from islet autoantigens, including insulin, in T1D. In addition, the CD-associated DQ2.5 and DQ8 alleles are unusual in their interactions with factors that regulate their peptide loading, invariant chain (Ii) and HLA-DM (DM). The same alleles, as well as other T1D DQ risk alleles (and Ag7) share nonpolar residues in place of Asp at β57 and prefer peptides that place acidic side chains in a pocket in the MHCII groove (P9). Antigen-presenting cells from T1D-susceptible mice and humans retain CLIP due to poor DM editing, although underlying mechanisms differ between species. We propose that these effects on peptide presentation make key contributions to CD and T1D pathogenesis.

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Section: Type 1 Diabetesmentioning

confidence: 99%

“…In transfected cells, expression of DM can aid CLIP release from A g7 (133). Moreover, A g7 expression is reduced in mutant APC lacking H2-DM, due to accelerated turnover (44). The surprising observation that NOD splenocytes nonetheless have increased levels of CLIP at the surface therefore suggests a CLIP exchange defect (134).…”

Section: Type 1 Diabetesmentioning

confidence: 99%

On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

Busch

Riva

Hadjinicolaou

et al. 2012

Expert Rev. Mol. Med.

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“…However, the γδ T cells still potentially might auto-present [8, 46]. We therefore examined the B:9-23-reactive γδ hybridomas themselves for the expression of the NOD-derived MHCII molecule, I-A g7 , using mAb RT1B (clone OX-6) [47], which recognizes this molecule [48, 49] as well as mouse I-A k and I-A s , and mAb M5/114 [50], which recognizes mouse I-A b,d,q and I-E d,k . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

γδ T cells recognize the insulin B:9–23 peptide antigen when it is dimerized through thiol oxidation

Aydintug

Zhang

Wang

et al. 2014

Molecular Immunology

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The insulin peptide B:9-23 is a natural antigen in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). In addition to αβ T cells and B cells, γδ T cells recognize the peptide and infiltrate the pancreatic islets where the peptide is produced within β cells. The peptide contains a cysteine in position 19 (Cys19), which is required for the γδ but not the αβ T cell response, and a tyrosine in position 16 (Tyr16), which is required for both. A peptide-specific mAb, tested along with the T cells, required neither of the two amino acids to bind the B:9-23 peptide. We found that γδ T cells require Cys19 because they recognize the peptide antigen in an oxidized state, in which the Cys19 thiols of two peptide molecules form a disulfide bond, creating a soluble homo-dimer. In contrast, αβ T cells recognize the peptide antigen as a reduced monomer, in complex with the MHCII molecule I-Ag7. Unlike the unstructured monomeric B:9-23 peptide, the γδ-stimulatory homo-dimer adopts a distinct secondary structure in solution, which differs from the secondary structure of the corresponding portion of the native insulin molecule. Tyr16 is required for this adopted structure of the dimerized insulin peptide as well as for the γδ response to it. This observation is consistent with the notion that γδ T cell recognition depends on the secondary structure of the dimerized insulin B:9-23 antigen.

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“…cDNAs of 3xflag-tagged WT and mutant (M98A) Ii[12] were cloned into MCS of pCDH vectors (T2A vector and dual promoter vector MSCV) purchased from System Bioscience (Mountain view, CA). Dual promoter vector EF1a was derived from MSCV vector by switching the positions of GFP and Ii.…”

Section: Methodsmentioning

confidence: 99%

“…M98A can improve the stability and abundance of a particular murine class II I-A g7 [12]). Two ubiquitous promoters-Murine Stem Cell Virus (MSCV) and the housekeeping Elongation Factor 1a (EF1a) were chosen, because they drive high transgene expression in human HSC[13, 14].…”

mentioning

confidence: 99%

Comparison of transduction efficiency among various lentiviruses containing GFP reporter in bone marrow hematopoietic stem cell transplantation

Wang

Rajasekaran

Hou

et al. 2013

Experimental Hematology

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HIV-derived lentiviral vectors have been widely employed to transduce non-dividing cells, such hematopoietic stem cells (HSC), in the setting of gene therapy. Here, we screened lentiviral vectors for their ability to drive expression of the murine MHC class II (MHCII) chaperone, invariant chain (Ii) and a GFP reporter. The vectors included T2A vector with T2A-separated Ii and GFP under the same MSCV promoter, dual-promoter vectors with separate promoters for Ii and GFP (called MSCV or EF1a according to the promoter driving Ii expression), and a vector with EF1a driving a fusion of Ii/GFP (called Fusion vector). T2A and MSCV induced highest levels of Ii and GFP expression, respectively, after direct transfection of 293T cells. All vectors except the Fusion vector drove expression of functional Ii, based on the enhancement of MHC II level, which is a known consequence of Ii expression. Comparing the vectors after they were packaged into lentiviruses and used to transduce 293T, we found MSCV and EF1a vectors mediated higher Ii and GFP expression. In ckit+ bone marrow (BM) cells, MSCV still induced the highest Ii and GFP expression, whereas EF1a only induced robust Ii expression. Regardless of the vector, both Ii and GFP levels were significantly reduced in BM cells compared to 293T cells. When in vivo expression was assessed in cells derived from MSCV-transduced BM-HSC, up to 80% of myeloid cells were GFP+, but no Ii expression was observed. In contrast, transplantation of EF1a-transduced BM-HSC led to much higher in vivo Ii expression. Thus, among those compared, dual-promoter vector-based lentivirus with the EF1a promoter driving the gene of interest is optimal for murine BM-HSC transduction.

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I-Ag7 is subject to post-translational chaperoning by CLIP

Cited by 11 publications

References 46 publications

On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

γδ T cells recognize the insulin B:9–23 peptide antigen when it is dimerized through thiol oxidation

Comparison of transduction efficiency among various lentiviruses containing GFP reporter in bone marrow hematopoietic stem cell transplantation

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