The Insulin-Specific T Cells of Nonobese Diabetic Mice Recognize a Weak MHC-Binding Segment in More Than One Form

Levisetti, Matteo; Suri, Anish; Petzold, Shirley J.; Unanue, Emil R.

doi:10.4049/jimmunol.178.10.6051

Cited by 98 publications

(124 citation statements)

References 46 publications

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“…The IC 50 values for the B:(9-23) peptide were measured in the 5-10 μM range at endosomal pH and the half-life of the complexes was less than two hours. Recently, a detailed analysis of the binding of this epitope to I-A g7 was made which confirmed these general findings and revealed several interesting new features [41]. First, the B:(9-23) peptide bound weakly to I-A g7 in two contiguous registers, using two neighboring binding core segments, as shown in Table 3.…”

Section: Weak Mhc Binding Peptides and Autoreactivity: The Case Of Thsupporting

confidence: 56%

“…Binding of Insulin B Chain Peptides b b Binding analysis of synthetic peptides to soluble I-A g7 . Binding studies were performed at pH 5.5 [41]. Replacement of the natural residues with lysines allowed for the identification of the P9-MHC contact amino acid.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, insulin T cells were sensitive to amino acid changes in either the flanks or the core segments of the peptide-affected binding and T cell responses [41].…”

Section: Weak Mhc Binding Peptides and Autoreactivity: The Case Of Thmentioning

confidence: 99%

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Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Suri

Levisetti

Unanue

2008

Current Opinion in Immunology

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One seminal aspect in autoimmune diabetes is antigen presentation of beta cell antigens by the diabetes-propensity class II histocompatibility molecules. The binding properties of I-A g7 molecules are reviewed here and an emphasis is placed on their selection of peptides with a highly specific sequence motif, in which one or more acidic amino acids are found at the carboxy end interacting at the P9 anchoring site of I-A g7 . The reasons for the central role of I-A g7 in the autoimmune response are analyzed. The insulin B chain segment 9-23 is a hot spot for T cell selection and a striking example of a weak MHC binding peptide that triggers autoreactivity.

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Section: Weak Mhc Binding Peptides and Autoreactivity: The Case Of Thsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Suri

Levisetti

Unanue

2008

Current Opinion in Immunology

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“…18,22,38,39 Recent studies in NOD mice showed that the InsB12-20 and InsB13-21 peptides are the core nonamers for IA g7 binding and induced T-cell reactivity in the NOD mouse. 40,41 Within InsB12-23 four binding registers exist capable of binding this molecule. Although in appearance IA g7 and HLA-DQ8 appear similar, yet there are subtle differences that may affect peptide binding and T-cell recognition.…”

Section: Discussionmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 transmolecules composed of a and b chains from DQ2 and DQ8 express unique b-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis-and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

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“…Each binding register creates a unique set of upward pointing amino acid side-chains for T-cell recognition and also exhibits a distinct binding affinity for MHC class II conferred by the downward-facing amino acids that occupy its binding pockets. The Unanue group first reported that B:9-23 can be presented by IA g7 in either R1 or R2 and that each register is recognized by a different set of B:9-23-spepcifc CD4 + T cells (8). In contrast, a separate study (9,10) reported that T cells recognize the B:9-23 peptide bound to IA g7 in R3, the weakest binding of the three registers.…”

mentioning

confidence: 99%

Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes

Yang¹,

Chow²,

Sosinowski

et al. 2014

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

109

149

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Previous studies in type 1 diabetes (T1D) in the nonobese diabetic mouse demonstrated that a crucial insulin epitope (B:9-23) is presented to diabetogenic CD4 T cells by IA g7 in a weakly bound register. The importance of antigenic peptides with low-affinity HLA binding in human autoimmune disease remains less clear. The objective of this study was to investigate T-cell responses to a lowaffinity self-epitope in subjects with T1D. HLA-DQ8 tetramers loaded with a modified insulin peptide designed to improve binding the lowaffinity register were used to visualize T-cell responses following in vitro stimulation. Positive responses were only detectable in T1D patients. Because the immunogenic register of B:9-23 presented by DQ8 has not been conclusively demonstrated, T-cell assays using substituted peptides and DQ8 constructs engineered to express and present B:9-23 in fixed binding registers were used to determine the immunogenic register of this peptide. Tetramer-positive T-cell clones isolated from T1D subjects that responded to stimulation by B:11-23 peptide and denatured insulin protein were conclusively shown to recognize B:11-23 bound to HLA-DQ8 in the low-affinity register 3. These T cells also responded to homologous peptides derived from microbial antigens, suggesting that their initial priming could occur via molecular mimicry. These results are in accord with prior observations from the nonobese diabetic mouse model, suggesting a mechanism shared by mouse and man through which T cells that recognize a weakly bound peptide can circumvent tolerance mechanisms and play a role in the initiation of autoimmune diseases, such as T1D.antigen presentation | self-antigen | MHCII tetramers T ype 1 diabetes (T1D) is a polygenic T-cell-mediated autoimmune disease with strong genetic linkages to the MHC class II and insulin promoter regions (1). Class II molecules are fundamental for CD4 + T-cell activation, whereas the insulin promoter polymorphism can modulate insulin levels in the thymus thereby influencing the threshold of selection for insulinspecific autoreactive T cells (2, 3). In the nonobese diabetic (NOD) mouse model of autoimmune mediated diabetes, insulinspecific IA g7 -restricted CD4 + T cells have been strongly implicated in β-cell destruction. In prediabetic NOD mice, 50% of the T-cell clones established from islet-infiltrating lymphocytes were insulin-specific and the majority of these clones recognized the insulin B:9-23 (B:9-23 SHLVEALYLVCGERG) epitope (4, 5). Moreover, substitution of a single residue in the B:9-23 region abrogated development of diabetes in a transgenic mouse model (6, 7). Thus, in the murine NOD model, the IA g7 -restricted B:9-23 epitope is considered to be pivotal in the development of diabetes.The position or "register" that B:9-23 occupies within the IA g7 binding groove has been a controversial but important question. At least three binding registers (R) have been considered, defined here by which B:9-23 amino acid occupies the first binding pocket (p1) position in the IA g7 ...

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The Insulin-Specific T Cells of Nonobese Diabetic Mice Recognize a Weak MHC-Binding Segment in More Than One Form

Cited by 98 publications

References 46 publications

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes

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