Cargando…
A mutagenesis study of autoantigen optimization for potential T1D vaccine design
A previously reported autoreactive antigen, termed the X-idiotype, isolated from a unique cell population in Type 1 diabetes (T1D) patients, was found to stimulate their CD4+ T cells. This antigen was previously determined to bind more favorably than insulin and its mimic (insulin superagonist) to H...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120010/ https://www.ncbi.nlm.nih.gov/pubmed/37040399 http://dx.doi.org/10.1073/pnas.2214430120 |
_version_ | 1785029106334695424 |
---|---|
author | Song, Yi Bell, David R. Ahmed, Rizwan Chan, Kevin C. Lee, Sangyun Hamad, Abdel Rahim A. Zhou, Ruhong |
author_facet | Song, Yi Bell, David R. Ahmed, Rizwan Chan, Kevin C. Lee, Sangyun Hamad, Abdel Rahim A. Zhou, Ruhong |
author_sort | Song, Yi |
collection | PubMed |
description | A previously reported autoreactive antigen, termed the X-idiotype, isolated from a unique cell population in Type 1 diabetes (T1D) patients, was found to stimulate their CD4+ T cells. This antigen was previously determined to bind more favorably than insulin and its mimic (insulin superagonist) to HLA-DQ8, supporting its strong role in CD4+ T cell activation. In this work, we probed HLA-X-idiotype-TCR binding and designed enhanced-reactive pHLA-TCR antigens using an in silico mutagenesis approach which we functionally validated by cell proliferation assays and flow cytometry. From a combination of single, double, and swap mutations, we identified antigen-binding sites p4 and p6 as potential mutation sites for HLA binding affinity enhancement. Site p6 is revealed to favor smaller but more hydrophobic residues than the native tyrosine, such as valine (Y6V) and isoleucine (Y6I), indicating a steric mechanism in binding affinity improvement. Meanwhile, site p4 methionine mutation to hydrophobic residues isoleucine (M4I) or leucine (M4L) modestly increases HLA binding affinity. Select p6 mutations to cysteine (Y6C) or isoleucine (Y6I) exhibit favorable TCR binding affinities, while a swap p5-p6 tyrosine–valine double mutant (V5Y_Y6V) and a p6-p7 glutamine–glutamine double mutant (Y6Q_Y7Q) exhibit enhanced HLA binding affinity but weakened TCR affinity. This work holds relevance to potential T1D antigen-based vaccine design and optimization. |
format | Online Article Text |
id | pubmed-10120010 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-101200102023-04-22 A mutagenesis study of autoantigen optimization for potential T1D vaccine design Song, Yi Bell, David R. Ahmed, Rizwan Chan, Kevin C. Lee, Sangyun Hamad, Abdel Rahim A. Zhou, Ruhong Proc Natl Acad Sci U S A Biological Sciences A previously reported autoreactive antigen, termed the X-idiotype, isolated from a unique cell population in Type 1 diabetes (T1D) patients, was found to stimulate their CD4+ T cells. This antigen was previously determined to bind more favorably than insulin and its mimic (insulin superagonist) to HLA-DQ8, supporting its strong role in CD4+ T cell activation. In this work, we probed HLA-X-idiotype-TCR binding and designed enhanced-reactive pHLA-TCR antigens using an in silico mutagenesis approach which we functionally validated by cell proliferation assays and flow cytometry. From a combination of single, double, and swap mutations, we identified antigen-binding sites p4 and p6 as potential mutation sites for HLA binding affinity enhancement. Site p6 is revealed to favor smaller but more hydrophobic residues than the native tyrosine, such as valine (Y6V) and isoleucine (Y6I), indicating a steric mechanism in binding affinity improvement. Meanwhile, site p4 methionine mutation to hydrophobic residues isoleucine (M4I) or leucine (M4L) modestly increases HLA binding affinity. Select p6 mutations to cysteine (Y6C) or isoleucine (Y6I) exhibit favorable TCR binding affinities, while a swap p5-p6 tyrosine–valine double mutant (V5Y_Y6V) and a p6-p7 glutamine–glutamine double mutant (Y6Q_Y7Q) exhibit enhanced HLA binding affinity but weakened TCR affinity. This work holds relevance to potential T1D antigen-based vaccine design and optimization. National Academy of Sciences 2023-04-11 2023-04-18 /pmc/articles/PMC10120010/ /pubmed/37040399 http://dx.doi.org/10.1073/pnas.2214430120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Song, Yi Bell, David R. Ahmed, Rizwan Chan, Kevin C. Lee, Sangyun Hamad, Abdel Rahim A. Zhou, Ruhong A mutagenesis study of autoantigen optimization for potential T1D vaccine design |
title | A mutagenesis study of autoantigen optimization for potential T1D vaccine design |
title_full | A mutagenesis study of autoantigen optimization for potential T1D vaccine design |
title_fullStr | A mutagenesis study of autoantigen optimization for potential T1D vaccine design |
title_full_unstemmed | A mutagenesis study of autoantigen optimization for potential T1D vaccine design |
title_short | A mutagenesis study of autoantigen optimization for potential T1D vaccine design |
title_sort | mutagenesis study of autoantigen optimization for potential t1d vaccine design |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120010/ https://www.ncbi.nlm.nih.gov/pubmed/37040399 http://dx.doi.org/10.1073/pnas.2214430120 |
work_keys_str_mv | AT songyi amutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT belldavidr amutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT ahmedrizwan amutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT chankevinc amutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT leesangyun amutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT hamadabdelrahima amutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT zhouruhong amutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT songyi mutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT belldavidr mutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT ahmedrizwan mutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT chankevinc mutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT leesangyun mutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT hamadabdelrahima mutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign AT zhouruhong mutagenesisstudyofautoantigenoptimizationforpotentialt1dvaccinedesign |