Naturally processed peptides from two disease-resistance-associated HLA-DR13 alleles show related sequence motifs and the effects of the dimorphism at position 86 of the HLA-DR beta chain.

Davenport, Miles P.; Quinn, Cheryl L.; Chicz, Roman M.; Green, Brian N.; Willis, Anthony C.; Lane, William S.; Bell, John I.; Hill, Adrian V. S.

doi:10.1073/pnas.92.14.6567

Cited by 103 publications

(92 citation statements)

References 25 publications

(23 reference statements)

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“…At the amino acid positions that comprise pocket 1, DR1401, DR1104, and DR1301 are completely identical. In agreement with our current observations, DR1104 and DR1301 have been shown to prefer Ile, Leu, and Val at this position (17,25).…”

Section: Discussionsupporting

confidence: 93%

“…DR1401, DR1104, and DR1301 are completely identical at the amino acid positions that comprise pocket 6, so binding preferences should be the same at this position. In agreement with our observations, DR1104 and DR1301 have been shown to prefer Arg, Lys, and His at this position (17,25).…”

Section: Discussionsupporting

confidence: 92%

“…Interestingly, Flu B 313-332 does not contain a particularly good motif for DR1401. However, if alanine could be accommodated at position 1, as has been reported for DR1301 (17), AKAIGNCPI (underlined) could bind. Similarly, we evaluated published peptide sequences containing putative DR1401 epitopes and found several that contain a motif consistent with our findings.…”

Section: Motif Analysis Of Peptides Containing Dr1401 Epitopesmentioning

confidence: 83%

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Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

James

Moustakas

Berger

et al. 2008

Molecular Immunology

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This study identified the peptide-binding motif of HLA-DRB1*1401 (DR1401). First, peptides containing DR1401 restricted epitopes were identified using tetramer guided epitope mapping. Among these, an influenza B peptide was selected for the motif study. After confirming the binding register for this peptide using a set of arginine substitutions, binding affinities were determined for 33 peptides derived from this influenza B sequence with single amino acid substitutions. The DR1401 peptide binding motif was deduced from the relative binding affinities of these peptides and confirmed by structural modeling. Pocket 1 demonstrated a preference for aliphatic anchor residues and methionine. Pocket 4 accommodated methionine and aliphatic residues, but also allowed some polar and charged amino acids. Pocket 6 preferred basic residues but also allowed some polar and aliphatic amino acids. Pocket 9 preferred aliphatic and aromatic amino acids and tolerated some polar residues but excluded all charged residues. Together these preferences define a distinct set of peptides that can be presented by DR1401. The resulting motif was used to verify T cell epitopes within the novel antigenic peptides identified by tetramer guided epitope mapping and within peptides from published reports that contain putative DR1401 epitopes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Section: Motif Analysis Of Peptides Containing Dr1401 Epitopesmentioning

confidence: 83%

See 1 more Smart Citation

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

James

Moustakas

Berger

et al. 2008

Molecular Immunology

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“…[19][20][21][22] On the other hand, T-cell responses against certain epitopes have been reported to associate either with benign or with severe and progressive infections. 23,24 In addition, immunodominant and promiscuous HLA class II-restricted epitopes have been reported for several pathogens, and their use has been proposed for the design of synthetic vaccines potentially effective in a wide proportion of the general population. [25][26][27][28][29] This approach is complicated in HCV infection by viral variability, because useful T-cell epitopes should also be located within conserved regions of the virus to elicit cross-reactive responses effective against all different HCV strains.…”

Section: Discussionmentioning

confidence: 99%

“…3). At least 1 T-cell line from each patient recognized the core sequence [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] showing that the epitope contained within this region is immunodominant for all patients studied (Figs. 1B and 3).…”

Section: Fine Specificity Of the T-cell Response To Core Ns3 Ns4 Amentioning

confidence: 99%

Conserved hepatitis C virus sequences are highly immunogenic for CD4+ T cells: Implications for vaccine development

et al. 1999

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The HLA class II-restricted T-cell response to hepatitis C virus (HCV) antigens is believed to influence the final outcome of hepatitis C, because it is vigorous in patients who recover from acute hepatitis C, but it is weak in those who develop a chronic infection. For this reason, exogenous stimulation of T-cell responses in chronic HCV infection may represent a strategy to cure patients with chronic hepatitis C by approximating the vigor of their T-cell reactivity to that of patients who succeed in recovering from hepatitis. It may also be a preventive approach to avoid spread of the virus by facilitating the development of a vigorous protective response at the very early stages of infection. T-cell-based vaccines composed of immunodominant, promiscuous, and conserved T-cell epitopes may represent a powerful tool to achieve optimal stimulation of the T-cell reactivity. To identify HLA class II-restricted T-cell epitopes useful for this purpose, 22 subjects with acute HCV infection were studied and followed for an average time of 29 months. Eight of them recovered from hepatitis, and 14 developed a chronic infection. Overlapping 20-mer peptides covering the entire core and NS4 antigens and a panel of peptides representing highly conserved regions of core, NS3, NS4, and NS5 were used. By direct peripheral blood T-cell stimulation and by finespecificity analysis of HCV-specific T-cell lines and clones, highly immunogenic T-cell epitopes were identified within core, NS3, and NS4. All these epitopes are immunodominant and highly conserved among the known HCV isolates. Moreover, they are promiscuous, because they can be presented to T cells by different HLA class II molecules. Immunodominance, sequence conservation, and promiscuity make these epitopes ideal components of preventive or therapeutic T-cell-based vaccines against HCV. (HEPATOL-OGY 1999;30:1088-1098.)The hepatitis C virus (HCV) is a RNA virus that can cause either acute self-limited infections or, more frequently, chronic liver cell injury leading to cirrhosis and hepatocellular carcinoma in a high proportion of cases. 1 The mechanisms responsible for persistence or viral clearance are still largely unknown. However, recent studies reported different patterns of proliferative T-cell response and cytokine production by antigen-specific CD4 ϩ T cells in patients with self-limited or chronically evolving HCV infection. [2][3][4] Patients with selflimited acute hepatitis show more vigorous peripheral blood proliferative T-cell responses to HCV proteins, predominantly sustained by Th1-like lymphocytes able to secrete proinflammatory cytokines (interferon gamma [IFN-␥] and interleukin-2 [IL-2]). Patients with chronic evolution of infection display weaker and less efficient proliferative T-cell responses suggesting that the intensity of the T-cell reactivity at the early stages of infection may be critical to limit the spread of the virus within the infected host and to keep viral replication under control. 2,3 In continuation of our previous studies suggestin...

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Complementarity and redundancy of the binding specificity of HLA-DRB1, -DRB3, -DRB4 and -DRB5 molecules

et al. 2001

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The second HLA‐DR molecules, which are encoded by loci different from HLA‐DRB1 are weakly polymorphic. Predominant alleles such as HLA‐DRB3*0101, HLA‐DRB4*0101 and HLA‐DRB5*0101 are therefore interesting targets to define antigenic peptides with major impact for the entire population. Strikingly, they have been poorly investigated. Thus we have characterized peptides from the major bee venom allergen that bind efficiently to these molecules and compared them to peptides specific for preponderant HLA‐DRB1 molecules. Interestingly, DRB5*0101 and DRB1*0701 molecules share four bindingpeptides and use some identical anchor residues. Similarities are also found between DRB3*0101 and its haplotype‐associated molecules DRB1*0301 and DRB1*1301. In sharp contrast, DRB4*0101 exhibits a unique binding specificity, which results from particular structural features of its peptide binding site. Yβ81 seems to alter the amino acid preferences of the P1 pocket, while Rβ71, Eβ74, Nβ26 and Cβ13 confer to the P4 pocket a unique topology. Our results show that the two HLA‐DR molecules expressed in most haplotypes studied here have mostly complementary binding patterns. Only haplotype HLA‐DR52 exhibits peptide binding redundancies. Finally our results document functional similarities among HLA‐DR molecules and allow us to propose peptide sequences that might be useful for bee venom immunotherapy.

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Naturally processed peptides from two disease-resistance-associated HLA-DR13 alleles show related sequence motifs and the effects of the dimorphism at position 86 of the HLA-DR beta chain.

Cited by 103 publications

References 25 publications

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

Conserved hepatitis C virus sequences are highly immunogenic for CD4+ T cells: Implications for vaccine development

Complementarity and redundancy of the binding specificity of HLA-DRB1, -DRB3, -DRB4 and -DRB5 molecules

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