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Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules

Major Histocompatibility Complex class I (MHC-I) molecules display self, viral or aberrant epitopic peptides to T cell receptors (TCRs), which employ interactions between complementarity-determining regions with both peptide and MHC-I heavy chain ‘framework’ residues to recognize specific Human Leuc...

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Autores principales: Papadaki, Georgia F., Ani, Omar, Florio, Tyler J., Young, Michael C., Danon, Julia N., Sun, Yi, Dersh, Devin, Sgourakis, Nikolaos G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9905809/
https://www.ncbi.nlm.nih.gov/pubmed/36761745
http://dx.doi.org/10.3389/fimmu.2023.1116906
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author Papadaki, Georgia F.
Ani, Omar
Florio, Tyler J.
Young, Michael C.
Danon, Julia N.
Sun, Yi
Dersh, Devin
Sgourakis, Nikolaos G.
author_facet Papadaki, Georgia F.
Ani, Omar
Florio, Tyler J.
Young, Michael C.
Danon, Julia N.
Sun, Yi
Dersh, Devin
Sgourakis, Nikolaos G.
author_sort Papadaki, Georgia F.
collection PubMed
description Major Histocompatibility Complex class I (MHC-I) molecules display self, viral or aberrant epitopic peptides to T cell receptors (TCRs), which employ interactions between complementarity-determining regions with both peptide and MHC-I heavy chain ‘framework’ residues to recognize specific Human Leucocyte Antigens (HLAs). The highly polymorphic nature of the HLA peptide-binding groove suggests a malleability of interactions within a common structural scaffold. Here, using structural data from peptide:MHC-I and pMHC:TCR structures, we first identify residues important for peptide and/or TCR binding. We then outline a fixed-backbone computational design approach for engineering synthetic molecules that combine peptide binding and TCR recognition surfaces from existing HLA allotypes. X-ray crystallography demonstrates that chimeric molecules bridging divergent HLA alleles can bind selected peptide antigens in a specified backbone conformation. Finally, in vitro tetramer staining and biophysical binding experiments using chimeric pMHC-I molecules presenting established antigens further demonstrate the requirement of TCR recognition on interactions with HLA framework residues, as opposed to interactions with peptide-centric Chimeric Antigen Receptors (CARs). Our results underscore a novel, structure-guided platform for developing synthetic HLA molecules with desired properties as screening probes for peptide-centric interactions with TCRs and other therapeutic modalities.
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spelling pubmed-99058092023-02-08 Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules Papadaki, Georgia F. Ani, Omar Florio, Tyler J. Young, Michael C. Danon, Julia N. Sun, Yi Dersh, Devin Sgourakis, Nikolaos G. Front Immunol Immunology Major Histocompatibility Complex class I (MHC-I) molecules display self, viral or aberrant epitopic peptides to T cell receptors (TCRs), which employ interactions between complementarity-determining regions with both peptide and MHC-I heavy chain ‘framework’ residues to recognize specific Human Leucocyte Antigens (HLAs). The highly polymorphic nature of the HLA peptide-binding groove suggests a malleability of interactions within a common structural scaffold. Here, using structural data from peptide:MHC-I and pMHC:TCR structures, we first identify residues important for peptide and/or TCR binding. We then outline a fixed-backbone computational design approach for engineering synthetic molecules that combine peptide binding and TCR recognition surfaces from existing HLA allotypes. X-ray crystallography demonstrates that chimeric molecules bridging divergent HLA alleles can bind selected peptide antigens in a specified backbone conformation. Finally, in vitro tetramer staining and biophysical binding experiments using chimeric pMHC-I molecules presenting established antigens further demonstrate the requirement of TCR recognition on interactions with HLA framework residues, as opposed to interactions with peptide-centric Chimeric Antigen Receptors (CARs). Our results underscore a novel, structure-guided platform for developing synthetic HLA molecules with desired properties as screening probes for peptide-centric interactions with TCRs and other therapeutic modalities. Frontiers Media S.A. 2023-01-25 /pmc/articles/PMC9905809/ /pubmed/36761745 http://dx.doi.org/10.3389/fimmu.2023.1116906 Text en Copyright © 2023 Papadaki, Ani, Florio, Young, Danon, Sun, Dersh and Sgourakis https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Papadaki, Georgia F.
Ani, Omar
Florio, Tyler J.
Young, Michael C.
Danon, Julia N.
Sun, Yi
Dersh, Devin
Sgourakis, Nikolaos G.
Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules
title Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules
title_full Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules
title_fullStr Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules
title_full_unstemmed Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules
title_short Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules
title_sort decoupling peptide binding from t cell receptor recognition with engineered chimeric mhc-i molecules
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9905809/
https://www.ncbi.nlm.nih.gov/pubmed/36761745
http://dx.doi.org/10.3389/fimmu.2023.1116906
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