Peptides Presented to the Immune System by the Murine Class II Major Histocompatibility Complex Molecule I-A
            <sub>d</sub>

Hunt, Donald F.; Michel, Hanspeter; Dickinson, Tracey; Shabanowitz, Jeffrey; Cox, Andrea L.; Sakaguchi, Kazuyasu; Appella, Ettore; Grey, Howard M.; Sette, Alessandro

doi:10.1126/science.1319610

Cited by 634 publications

(367 citation statements)

References 29 publications

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“…Several attempts have been made to identify the natural peptides bound to MHC molecules, starting from the pioneering studies of Rammensee [1][2][3], and continuing with the introduction of mass spectrometry [4,5]. In our own experience, we have evaluated naturally processed peptides selected by various murine (I-A k , I-A d , I-E k , I-E p , I-A g7 , I-A g7PD and K d ) and human (DQ8) MHC molecules.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

Suri

Levisetti

Unanue

2008

Current Opinion in Immunology

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“…Detailed analyses of naturally processed peptides from class I and II MHC molecules have revealed their general features; for example, the lengths of naturally processed peptides selected by class I MHC molecules are usually restricted to 8-10-mers whereas those selected by class II MHC molecules are longer and more variable, usually 14-24-mers [5,[11][12][13]. More importantly, analyses of naturally processed peptides addresses key issues regarding the specificity of peptideselection among closely related MHC molecules, not evident in prior studies involving synthetic peptide libraries [3,[10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…More importantly, analyses of naturally processed peptides addresses key issues regarding the specificity of peptideselection among closely related MHC molecules, not evident in prior studies involving synthetic peptide libraries [3,[10][11][12][13][14]. Furthermore, binding and mutational analyses of naturally processed peptides have identified critical anchor residues that interact with the binding pockets of the MHC molecules and, thus, help establish the preferred binding motif.…”

Section: Introductionmentioning

confidence: 99%

Identification of naturally processed peptides bound to the class I MHC molecule H‐2K^d of normal and TAP‐deficient cells

et al. 2006

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This report details the biochemical features of natural peptides selected by the H-2K d class I MHC molecule. In normal cell lines, the length of the naturally processed peptides ranged from 8 to 18 amino acids, although the majority were 9-mers (16% were longer than nine residues). The binding motif for the 9-mer peptides was dominated by the presence of a tyrosine at P2 and an isoleucine/leucine at the P9 position. The P2 residue contributed most towards binding; and the short peptides bound better and formed longer-lived cell surface complexes than the long peptides, which bound poorly and dissociated rapidly. The longer peptides did not exhibit this strictly defined motif. Trimming the long peptides to their shorter forms did not enhance binding and conversely, extending the 9-mer peptides did not decrease binding. The long peptides were present on the cell-surface bound to H-2K d (Kd) and were not intermediate products of the class I MHC processing pathway. Finally, in two different TAP-deficient cells the long peptides were the dominant species, which suggested that TAPindependent pathways selected for long peptides by class I MHC molecules.

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“…The open ends of the MHC class II peptide-binding groove allow peptides of various lengths to be presented. Accordingly, dominant peptides eluted from MHC class II are not restricted in length, but rather are present as nested sets that share identical, MHC-binding, core sequences with various lengths of flanking residues [25][26][27]. The N-and C-terminal residues of these nested sets reflect the action of specific endopeptidases and exopeptidases; presumably, differential activities of these enzymes will affect the relative quantity of each component within the nested sets [28].…”

mentioning

confidence: 99%

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

Dai¹,

Jensen²,

Marrero³

et al. 2008

Eur J Immunol

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A diabetes-associated peptide in the glutamic acid decarboxylase 65 (GAD65) molecule, p524-543, activates two distinct populations of T cells, which apparently play opposite roles in the development of diabetes in NOD mice. By comparing the fine specificity of these two T cell repertoires using a nested set of truncated peptides that cover the p524-543 region, we found, surprisingly, that all clones recognized the same core within this peptide, p530-539. The core itself was non-immunogenic, but the residues flanking this shared sequence played the crucial role in selecting T cells to activate. A peptide missing N-terminal flanking residues at position 528 and 529 was stimulatory in NOD but not in MHC-matched, NODresistant (NOR) mice, suggesting that a protective response in the resistant mice may require T cell recognition of one or more of the N-terminal flanking residues. T cell repertoire studies demonstrated selective clonal expansions within the BV4 TCR family that dominates the p524-543 response in NOD but not in NOR mice. These data suggest that processing or trimming events affecting T cell recognition of very few flanking residues of diabetes-associated determinants might be involved in the protective response in NOR mice.Key words: Antigens/peptides/epitopes Á Autoimmune Á GAD65 Á T cell repertoire IntroductionProcessing and presentation of islet antigens on I-A g7 molecules is a crucial aspect in the emergence of spontaneous type 1 diabetes (T1D) in NOD mice. How the peptide-binding motif of I-A g7 relates to the selection and processing of peptide determinants and subsequent repertoire choice in this mouse strain and its related strains remains unresolved. Several autoantigens have been defined in type 1 diabetes (T1D) using antigen-specific antibody and/or T cell assays, including glutamic acid decarboxylase 65 (GAD65), proinsulin and insulin, insulinoma-like antigen 2 (IA-2), and insulin-specific glucose-6-phosphatase catalytic subunitrelated protein (IGRP). In NOD mice, several peptides from these autoantigens have been identified as targets of T cell responses. These include GAD65 p524-543 and p246-266 [1, 2], GAD65 p206-220 and p286-300 [3], insulin B chain p9-23 [4,5], proinsulin p24-33 (proinsulin II p48-57) [6],, and insulin-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) p206-214 [8]. Extensive analysis of TCR BV gene usage and CDR3 sequences have demonstrated that the early islet-infiltrating T cell clonal expansion is restricted to distinct BV families, e.g., BV4 [9], BV2, BV12, BV14 [10], BV13 [11], BV8.2 [12], and BV1 [13]. This indicates that selective clonal expansion of antigen-specific T cells is one characteristic of the initial inflammatory response in the islets. A recombinant congenic strain, which is NOD-resistant (NOR) and derives *88% of its genome from the NOD strain, including the I-A g7 MHC haplotype, was produced adventitiously at the Jackson Laboratory [14], and can be used as a control strain, since NOR mice are insulitis resistant and diabetes ...

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Peptides Presented to the Immune System by the Murine Class II Major Histocompatibility Complex Molecule I-A _d

Cited by 634 publications

References 29 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?

Identification of naturally processed peptides bound to the class I MHC molecule H‐2K^d of normal and TAP‐deficient cells

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

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Peptides Presented to the Immune System by the Murine Class II Major Histocompatibility Complex Molecule I-A d

Cited by 634 publications

References 29 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?

Identification of naturally processed peptides bound to the class I MHC molecule H‐2Kd of normal and TAP‐deficient cells

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

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Peptides Presented to the Immune System by the Murine Class II Major Histocompatibility Complex Molecule I-A _d

Identification of naturally processed peptides bound to the class I MHC molecule H‐2K^d of normal and TAP‐deficient cells