Dataset Information

Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses.

ABSTRACT: Non-natural modifications are widely introduced into peptides to improve their therapeutic efficacy, but their impact on immunogenicity remains largely unknown. As the CD4 T-cell response is a key factor in triggering immunogenicity, we investigated the effect of introducing D-amino acids (Daa), amino isobutyric acid (Aib), N-methylation, C_α-methylation, reduced amide, and peptoid bonds into an immunoprevalent T-cell epitope on binding to a set of HLA-DR molecules, recognition, and priming of human T cells. Modifications are differentially accepted at multiple positions, but are all tolerated in the flanking regions. Introduction of Aib and Daa in the binding core had the most deleterious effect on binding to HLA-DR molecules and T-cell activation. Their introduction at the positions close to the P1 anchor residue abolished T-cell priming, suggesting they might be sufficient to dampen peptide immunogenicity. Other modifications led to variable effects on binding to HLA-DR molecules and T-cell reactivity, but none exhibited an increased ability to stimulate T cells. Altogether, non-natural modifications appear generally to diminish binding to HLA-DR molecules and hence T-cell stimulation. These data might guide the design of therapeutic peptides to make them less immunogenic.

SUBMITTER: Azam A

PROVIDER: S-EPMC7991740 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses.

Azam Aurélien A Mallart Sergio S Illiano Stephane S Duclos Olivier O Prades Catherine C Maillère Bernard B

Frontiers in immunology 20210311

Non-natural modifications are widely introduced into peptides to improve their therapeutic efficacy, but their impact on immunogenicity remains largely unknown. As the CD4 T-cell response is a key factor in triggering immunogenicity, we investigated the effect of introducing D-amino acids (Daa), amino isobutyric acid (Aib), N-methylation, C<sub>α</sub>-methylation, reduced amide, and peptoid bonds into an immunoprevalent T-cell epitope on binding to a set of HLA-DR molecules, recognition, and pr ...[more]

PMID: 33777029

Similar Datasets

Project description:Background: Due to the similarity between the dengue (DENV) and the Japanese encephalitis virus (JEV) there is potential for immune cross-reaction. We sought to identify T cell epitopes that are specific to JEV and do not cross react with DENV. Methodology: 20mer peptides were synthesized from regions which showed >90% conservation. Using IFNγ cultured ELISpot assays, we investigated JEV-specific T cell responses in DENV- and JEV- non-immune individuals (DENV-JEV- = 21), JEV seronegative and had not received the JE vaccine, but who were DENV seropositive (DENV+JEV- = 22), JEV+(seropositive for JEV and had received the JE vaccine), but seronegative for DENV (DENV-JEV+ = 23). We further assessed the responses to these peptides by undertaking ex vivo IFNγ assays and flow cytometry. Results: None of DENV-JEV- individuals responded to any of the 20 JEV-specific peptides. High frequency of responses was seen to 6/20 peptides by individuals who were JEV+ but DENV-, where over 75% of the individuals responded to at least one peptide. P34 was the most immunogenic peptide, recognized by 20/23 (86.9%) individuals who were DENV-JEV+, followed by peptide 3 and peptide 7 recognized by 19/23 (82.6%). Peptide 34 from the NS2a region, showed <25% homology with any flaviviruses, and <20% homology with any DENV serotype. Peptide 20 and 32, which were also from the non-structural protein regions, showed <25% homology with DENV. Ex vivo responses to these peptides were less frequent, with only 40% of individuals responding to peptide 34 and 16-28% to other peptides, probably as 5/6 peptides were recognized by CD4+ T cells. Discussion: We identified six highly conserved, T cell epitopes which are highly specific for JEV, in the Sri Lankan population. Since both JEV and DENV co-circulate in the same regions and since both JE and dengue vaccines are likely to be co-administered in the same geographical regions in future, these JEV-specific T cell epitopes would be useful to study JEV-specific T cell responses, in order to further understand how DENV and JEV-specific cellular immune responses influence each other.

Dataset Information

Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses.

Publications

Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets