Ovalbumin(323−339) Peptide Binds to the Major Histocompatibility Complex Class II I-A<sup>d</sup>Protein Using Two Functionally Distinct Registers

McFarland, Benjamin J.; Sant, Andrea J.; Lybrand, Terry P.; Beeson, Craig C.

doi:10.1021/bi991393l

Cited by 72 publications

(67 citation statements)

References 44 publications

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“…Various OVA and FMD-V peptides have previously been used as immunogenic epitopes to define antigen presentation, the kinetics of peptide-MHC binding, and assess antibody responses of cattle and mice [3,4,7,11,17,22,31]. FMD-VP2 and VP4, for example, were both demonstrated to bind with high affinity to BoLA-DRB3*1101 and BoLA-DRB3*0201, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Several self-peptides (BoLA-DQ and fibrinogen fragments), and non-self peptides (sperm whale myoglobin and mycobacterium heat shock protein fragments) previously eluted from BoLA-DRB3*2703 molecules were selected for initial study based on sequences derived from mass spectrometry analysis of pooled peptides [26]. The assumption being that one or more of these peptides would bind with high affinity to [17,22] and two viral peptides from the foot and mouth disease virus (FMDV), including VP2 74-88 and VP4 20-34 [7] were synthesized as competitor peptides (Tab. I).…”

Section: Peptidesmentioning

confidence: 99%

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Biological effect of varying peptide binding affinity to the BoLA-DRB32703* allele

2003

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-MHC class I and II molecules are immunoregulatory cell surface glycoproteins, which selectively bind to and present antigenic peptides to T-lymphocytes. Murine and human studies show that variable peptide binding affinity to MHC II molecules influences Th1/Th2 responses by inducing distinctive cytokine expression. To examine the biological effects of peptide binding affinity to bovine MHC (BoLA), various self peptides (BoLA-DQ and fibrinogen fragments) and non-self peptides from ovalbumin (OVA), as well as VP2 and VP4 peptides from foot and mouth disease virus (FMD-V) were used to (1) determine binding affinities to the BoLA-DRB3*2703 allele, previously associated with mastitis susceptibility and (2) determine whether peptide binding affinity influences T-lymphocyte function. Peptide binding affinity was determined by a competitive assay using high affinity biotinylated self-peptide incubated with purified BoLA-DRB3*2703 in the presence of various concentrations of competing peptides. The concentrations of non-self peptide required to inhibit self-peptide binding by 50% (IC50) were variable, ranging from 26.92 to > 320 µM. Peptide-specific T-lymphocyte function was determined by measuring DNA synthesis, cell division, and IFN-γ production in cultures of mononuclear cells from a BoLA-DRB3*2703 homozygous cow. When compared to nonstimulated control cultures, differences in lymphocyte function were observed for all of the assessed parameters; however, peptide-binding affinity did not always account for the observed differences in lymphocyte function. bovine / MHC class II / peptide binding affinity / lymphocyte function

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Section: Discussionmentioning

confidence: 99%

Section: Peptidesmentioning

confidence: 99%

Biological effect of varying peptide binding affinity to the BoLA-DRB32703* allele

2003

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“…On the other hand, it is also possible that a single peptide containing multiple anchors might bind a single MHC class II allele with distinct registers and thus generate different antigenic MHC class II-peptide conformers, each recognized by a specific set of TCR [20,22,45].…”

Section: Discussionmentioning

confidence: 99%

“…It is thus possible that a peptide, which contains multiple predicted anchor residues, might slide forward and backward in the MHC class II groove, assuming different binding registers, only one of which is optimal for the recognition by a specific TCR. This is called peptide register shifting within the MHC groove [19][20][21][22] and may represent an additional element that contribute to the difficulty in detecting CD4 1 T cells by MHC class II tetramers because it would result in the generation of tetramers with each arm made of a different peptide-MHC conformer. This, in turn, would decrease the overall avidity of the peptide-MHC class II tetramer for its cognate TCR, which would fall below a threshold compatible with the binding of soluble tetramers to the specific T cells.…”

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confidence: 99%

“…As described by James et al [44], promiscuous peptides that bear different anchors were found to contain multiple epitopes, each binding in a monogamous way a specific HLA-DR allele. Therefore, these peptides do not represent real promiscuous epitopes, but rather a linear array of different monogamous epitopes.On the other hand, it is also possible that a single peptide containing multiple anchors might bind a single MHC class II allele with distinct registers and thus generate different antigenic MHC class II-peptide conformers, each recognized by a specific set of TCR [20,22,45].In line with this observation, our data are consistent with the possibility that the MAGE-A3-derived p57 and p58 peptides, which are predicted to contain different putative P1 anchors for the HLA-DR Ã 1101 allele, bind into the HLA-DR groove in different registers, generating different peptide-HLA-DR conformers. By reducing the number of putative anchor residues predicted in the promiscuous peptides, therefore minimizing the number of different registers that the peptide can assume into the MHC class II groove, we show that it is possible to generate functional HLA-DR Ã 1101 tetramers that bind the specific TCR.…”

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The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

et al. 2010

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Detection of CD4 1 T cells specific for tumor-associated antigens is critical to investigate the spontaneous tumor immunosurveillance and to monitor immunotherapy protocols in patients. We investigated the ability of HLA-DR*1101 multimers to detect CD4 1 T cells specific for three highly promiscuous MAGE-A3 derived peptides: (p39), MAGE-A3 281-295 (p57) and MAGE-A3 286-300 (p58). Tetramers stained specific CD4 1 T cells only when loaded with p39, although all peptides activated the specific T cells when presented by plasticbound HLA-DR*1101 monomers. This suggested that tetramer staining ability was determined by the mode rather than the affinity of peptide binding to HLA-DR*1101. We hypothesized that peptides should bear a single P1 anchor residue to bind all arms of the multimer in a homogeneous register to generate peptide-HLA-DR conformers with maximal avidity. Bioinformatics analysis indicated that p39 contained one putative P1 anchor residue, whereas the other two peptides contained multiple ones. Designing p57 and p58 analogues containing a single anchor residue generated HLA-DR*1101 tetramers that stained specific CD4 1 T cells. Producing HLA-DR*1101 monomers linked with the optimized MAGE-A3 analogues, but not with the original epitopes, further improved tetramer efficiency. Optimization of CD4 1 T-cell epitope-binding registers is thus critical to generate functional HLA-DR tetramers.Key words: Anchor residues . HLA-DR Ã 1101 . MAGE-A3 . MHC tetramers . Tumor antigens Supporting Information available online IntroductionAnimal studies have clearly shown the critical role for CD4 1 T cells in anti-tumor immune response; nevertheless, little is known as yet about spontaneous tumor-specific CD4 1 T-cell responses in patients [1,2]. This knowledge would be instrumental to the definition of the mechanisms underlying tumor immunosurveillance and, possibly, tumor escape, as well as for the correct design of optimal vaccination strategies.CD4 1 T-cell responses specific for tumor associated antigens (TAA) can be investigated at the single cell level by using soluble [3][4][5][6]. The identification of primary antigen-specific CD4 1 T cells by peptide-pulsed MHC class II tetramers seems, however, less straightforward than that of CD8 1 T cells by peptide-loaded MHC class I tetramers [7,8]. Several biological and structural characteristics of the CD4 1 T-cell response that differ from those displayed by the CD8 1 one seem to affect the capacity of MHC class II tetramers to optimally stain specific CD4 1 T cells ex vivo: (i) the lower frequency of peptide-specific CD4 1 T cells, (ii) their apparent lower affinity for the peptide-MHC class II complexes [9][10][11][12][13], and (iii) the requirement for an activation-induced TCR reorganization to bind with sufficient avidity cognate peptide-MHC class II tetramers [12,14,15].Furthermore, the open structure of the MHC class II molecules allows peptides as long as 20 aa to extend out of the binding groove at both ends [16][17][18]. It is thus possible that a peptide,...

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Emerging principles for the design of promiscuous HLA-DR-restricted peptides: an example from the major bee venom allergen

et al. 2002

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Mechanisms underlying successful immunotherapy of allergic patients operate at the level of CD4+ helper T cells. T cell epitopes from allergens may thus constitute interesting molecules for immunotherapy, provided they are efficient for all patients and are not recognized by IgE. In an attempt to define such peptides for allergy to bee venom, we have investigated the capacity ofpeptides encompassing the sequence of the major bee venom allergen to stimulate PBMC from allergic patients and to react specifically with their IgE. The region 77–110 emerged as the most frequently T cell stimulating. We then analyzed the binding modes of the sequence 81–97 for ten different HLA‐DR molecules and introduced punctual mutations to enhance the peptide affinity for these molecules. Six different modes have been identified on the sequence 81–97, one mode being common to eight HLA‐DR molecules. Four HLA‐DR molecules can bind the P85–97 peptide by two different modes with an equivalent affinity. The peptide N89L has a higher affinity for DRB1*0301 and DRB3*0101 and remains as active as the native peptide towards the other HLA‐DR molecules.

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Ovalbumin(323−339) Peptide Binds to the Major Histocompatibility Complex Class II I-A^dProtein Using Two Functionally Distinct Registers

Cited by 72 publications

References 44 publications

Biological effect of varying peptide binding affinity to the BoLA-DRB32703* allele

Biological effect of varying peptide binding affinity to the BoLA-DRB32703* allele

The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

Emerging principles for the design of promiscuous HLA-DR-restricted peptides: an example from the major bee venom allergen

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Ovalbumin(323−339) Peptide Binds to the Major Histocompatibility Complex Class II I-AdProtein Using Two Functionally Distinct Registers

Cited by 72 publications

References 44 publications

Biological effect of varying peptide binding affinity to the BoLA-DRB3*2703 allele

Biological effect of varying peptide binding affinity to the BoLA-DRB3*2703 allele

The CD4+ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

Emerging principles for the design of promiscuous HLA-DR-restricted peptides: an example from the major bee venom allergen

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Ovalbumin(323−339) Peptide Binds to the Major Histocompatibility Complex Class II I-A^dProtein Using Two Functionally Distinct Registers

Biological effect of varying peptide binding affinity to the BoLA-DRB32703* allele

Biological effect of varying peptide binding affinity to the BoLA-DRB32703* allele

The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides