N-terminal elongation of a peptide determinant beyond the first primary anchor improves binding to H-2 I-Ad and HLA-DR1 by backbone-dependent and aromatic side chain-dependent interactions, respectively

Bartnes, Kristian; León, Francisco; Briand, Jean‐Paul; Travers, Paul; Hannestad, Kristian

doi:10.1002/(sici)1521-4141(199901)29:01<189::aid-immu189>3.0.co;2-x

Cited by 16 publications

(16 citation statements)

References 36 publications

(37 reference statements)

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“…The presence of Lys at position 33 is, however, less critical as the p21-Lys33Ala analog peptide maintains T cell activation properties. Moreover, the fact that Gly23Thr and Gly32Thr mutants of p21-35 significantly decreased T cell proliferative response demonstrates that residues outside the motif sequence may also substantially affect peptide binding to MHC II molecules, and as such exert an influence on the T cell response [24].…”

Section: Discussionmentioning

confidence: 99%

Major T cell epitope-containing peptides can elicit strong antibody responses

Toussaint

Elst

et al. 2000

Eur. J. Immunol.

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Section: Discussionmentioning

confidence: 99%

Major T cell epitope-containing peptides can elicit strong antibody responses

Toussaint

Elst

et al. 2000

Eur. J. Immunol.

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“…Ile 28 , therefore, might be a critical residue for MHC class II anchoring of p21-35. Flanking residues influence peptide T cell activation properties (32). Significant reductions in T cell response were observed for some haplotypes, particularly H-2 k mice, in which residue Arg 31 completely abrogated the T cell response (Fig.…”

Section: Ile 28 Is Critical For T Cell Responses In Different Mhc Hapmentioning

confidence: 94%

TheDermatophagoides pteronyssinusGroup 2 Allergen Contains a Universally Immunogenic T Cell Epitope

Elst

Carlier

et al. 2002

The Journal of Immunology

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The use of T cell epitope-containing peptides for the induction of anergy in allergen sensitization is limited by genetic restriction that could be circumvented by using universally immunogenic epitopes. We attempted to identify such epitopes on Dermatophagoides pteronyssinus group 2 allergen (Der p 2), a major allergen of D. pteronyssinus T cells from BALB/c (H-2d), C57BL/6 (H-2b), C3H (H-2k), and SJL (H-2s) mice that were immunized with rDer p 2, recognized an immunodominant region encompassing residues 21–35. A synthetic 21–35 peptide (p21–35) induced strong dose-dependent in vitro T cell proliferation with cells of the four mouse strains and required processing for MHC class II presentation. Substitution of Ile28 with Ala resulted in reduction of T cell proliferation in each strain. Ile28 could represent an important MHC class II anchoring residue for T cell response to p21–35. An immunodominant T cell epitope of Der p 2 therefore behaves as a universal epitope and could be a suitable candidate for T cell anergy induction.

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“…Natural processing gives rise to large nested sets of peptides that are bound to HLA class II molecules through the same core motif, but they are variably extended and truncated at the NH 2 -and COOH-termini (11). The NH 2 -and COOH-terminus peptide flanking residues (PFRs) can have potent effects on HLA binding and activation of CD4 T-cell clones (12)(13)(14). For example, Carson et al have shown that CD4 T-cell clones specific for the I-Ak immunodominant epitope of hen egg lysozyme (HEL) 52-61 are often entirely dependent upon, and specific for, COOH-terminal PFRs that lie outside the core MHCbinding region (14).…”

Section: Introductionmentioning

confidence: 99%

Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4

Peakman¹,

Stevens²,

Lohmann³

et al. 1999

J. Clin. Invest.

131

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During immune responses, antigen-presenting cells (APCs) process antigens and present peptide epitopes complexed with human leukocyte antigen (HLA) molecules. CD4 cells recognize these naturally processed and presented epitopes (NPPEs) bound to HLA class II molecules. Epitope identification is important for developing diagnostic and therapeutic tools for immune-mediated diseases and providing insight into their etiology, but current approaches overlook effects of natural processing on epitope selection. We have developed a technique to identify NPPEs using mass spectrometry (MS) after antigen is targeted onto APCs using a lectin-based antigen delivery system (ADS). We applied the technique to identify NPPEs of the intracellular domain of the type 1 diabetes mellitus-associated (type 1 DMassociated) autoantigen insulinoma-associated-2 (IA-2ic), presented by HLA-DR4 (0401). IA-2ic-derived NPPEs eluted from HLA-DR4 constitute 6 sets of peptides nested around distinct core regions. Synthetic peptides based on these regions bind HLA-DR4 and elicit primary T-cell proliferation frequently in HLA-DR4-positive type 1 DM patients, but rarely in non-HLA-DR4 patients, and in none of the HLA-DR4 nondiabetic controls we tested. This flexible, direct approach identifies an HLA allele-specific map of NPPEs for any antigen, presented by any HLA class II molecule. This method should enable a greater understanding of epitope selection and lead to the generation of sensitive and specific reagents for detecting autoreactive T cells.J. Clin. Invest. 104:1449-1457(1999 significantly enhance epitope recognition by CD4 T cells. For these reasons, we elected to develop a system for the direct identification of peptides naturally processed from specific Ag's and presented by HLA class II molecules as NPPEs recognized by CD4 T cells. We have applied the new technology to the prototypic organ-specific autoimmune disease, type 1 diabetes mellitus (DM), in which immune responses to numerous islet cell autoantigens occur on a distinctive genetic background, notably the possession of HLA-DRB1*0401, DQA1*0301/DQB1*0302 [DQ3.2] genotypes (15,16). In the present study we have focused on the islet cell autoantigen insulinoma-associated-2 (IA-2), one of a family of protein tyrosine phosphatases (PTPs) (17). Autoantibodies against these PTPs are directed toward the intracellular domain (IA-2ic), almost without exception (18), and are associated with rapid progression to diabetes in high-risk subjects (19). In the present study we identify NPPEs of IA-2ic bound to HLA-DR4 (0401) and demonstrate that synthetic peptides based on these are sensitive and specific reagents in the detection of autoreactive T cells in HLA-DR4 type 1 DM patients. MethodsSubjects. Fresh heparinized and clotted blood samples were obtained from 21 Caucasian type 1 DM patients (median age 20 years, range 6-42 years) recruited a median of 8 weeks after diagnosis (range 1-28 weeks). All had acute onset of symptoms, ketosis, and required insulin from diagnosis. Samples were also col...

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N-terminal elongation of a peptide determinant beyond the first primary anchor improves binding to H-2 I-Ad and HLA-DR1 by backbone-dependent and aromatic side chain-dependent interactions, respectively

Cited by 16 publications

References 36 publications

Major T cell epitope-containing peptides can elicit strong antibody responses

Major T cell epitope-containing peptides can elicit strong antibody responses

TheDermatophagoides pteronyssinusGroup 2 Allergen Contains a Universally Immunogenic T Cell Epitope

Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4

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