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Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition

Mycobacterium tuberculosis/human immunodeficiency virus (MTB/HIV) coinfection presents a special challenge to the prevention and treatment of tuberculosis and HIV/AIDS. Adoptive transfer of high-affinity T cell receptor (TCR) gene-modified T cells against MTB and HIV antigens is a promising approach...

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Autores principales: Zhou, Chao-Ying, Wang, Rui-Ning, Wen, Qian, He, Wen-Ting, Zhang, Shi-Meng, Du, Xia-Lin, Yang, Jia-Hui, Ma, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561015/
https://www.ncbi.nlm.nih.gov/pubmed/28861087
http://dx.doi.org/10.3389/fimmu.2017.00983
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author Zhou, Chao-Ying
Wang, Rui-Ning
Wen, Qian
He, Wen-Ting
Zhang, Shi-Meng
Du, Xia-Lin
Yang, Jia-Hui
Ma, Li
author_facet Zhou, Chao-Ying
Wang, Rui-Ning
Wen, Qian
He, Wen-Ting
Zhang, Shi-Meng
Du, Xia-Lin
Yang, Jia-Hui
Ma, Li
author_sort Zhou, Chao-Ying
collection PubMed
description Mycobacterium tuberculosis/human immunodeficiency virus (MTB/HIV) coinfection presents a special challenge to the prevention and treatment of tuberculosis and HIV/AIDS. Adoptive transfer of high-affinity T cell receptor (TCR) gene-modified T cells against MTB and HIV antigens is a promising approach to treating MTB/HIV coinfected patients whose cellular immunity is obviously disordered. We have previously successfully identified that a bispecific TCR screened out from peripheral blood mononuclear cells of a HLA-A*0201(+) healthy individual using the complementarity determining region 3 (CDR3) spectratype analysis recognizes both MTB Ag85B(199–207) and HIV-1 Env(120–128) peptide. However, it has not been known how residues on CDR3 loops, which have been shown to play a leading role in antigen binding and specificity contribute to the bispecific TCR contact with the peptide–major histocompatibility complex (MHC) complexes. In this study, we provided an extensive investigation of residues in the predicted CDR3 of the bispecific TCR beta (β) chain using alanine scanning mutagenesis. Our data showed that three of the five substituted residues (G115A, T116A, A117G) in CDR3β of the bispecific TCR caused a significantly diminished T cell response to antigen, whereas the remaining two substituted residues (D114A, S118A) resulted in completely eliminated response, thus identifying the two residues that were particularly critical for the recognition of peptide–MHC in the bispecific TCR. These findings will provide an imperative foundation for generating an improved high-affinity bispecific TCR for use in T cell adoptive immunotherapy for MTB/HIV coinfected individuals.
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spelling pubmed-55610152017-08-31 Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition Zhou, Chao-Ying Wang, Rui-Ning Wen, Qian He, Wen-Ting Zhang, Shi-Meng Du, Xia-Lin Yang, Jia-Hui Ma, Li Front Immunol Immunology Mycobacterium tuberculosis/human immunodeficiency virus (MTB/HIV) coinfection presents a special challenge to the prevention and treatment of tuberculosis and HIV/AIDS. Adoptive transfer of high-affinity T cell receptor (TCR) gene-modified T cells against MTB and HIV antigens is a promising approach to treating MTB/HIV coinfected patients whose cellular immunity is obviously disordered. We have previously successfully identified that a bispecific TCR screened out from peripheral blood mononuclear cells of a HLA-A*0201(+) healthy individual using the complementarity determining region 3 (CDR3) spectratype analysis recognizes both MTB Ag85B(199–207) and HIV-1 Env(120–128) peptide. However, it has not been known how residues on CDR3 loops, which have been shown to play a leading role in antigen binding and specificity contribute to the bispecific TCR contact with the peptide–major histocompatibility complex (MHC) complexes. In this study, we provided an extensive investigation of residues in the predicted CDR3 of the bispecific TCR beta (β) chain using alanine scanning mutagenesis. Our data showed that three of the five substituted residues (G115A, T116A, A117G) in CDR3β of the bispecific TCR caused a significantly diminished T cell response to antigen, whereas the remaining two substituted residues (D114A, S118A) resulted in completely eliminated response, thus identifying the two residues that were particularly critical for the recognition of peptide–MHC in the bispecific TCR. These findings will provide an imperative foundation for generating an improved high-affinity bispecific TCR for use in T cell adoptive immunotherapy for MTB/HIV coinfected individuals. Frontiers Media S.A. 2017-08-16 /pmc/articles/PMC5561015/ /pubmed/28861087 http://dx.doi.org/10.3389/fimmu.2017.00983 Text en Copyright © 2017 Zhou, Wang, Wen, He, Zhang, Du, Yang and Ma. http://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) or licensor 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
Zhou, Chao-Ying
Wang, Rui-Ning
Wen, Qian
He, Wen-Ting
Zhang, Shi-Meng
Du, Xia-Lin
Yang, Jia-Hui
Ma, Li
Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition
title Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition
title_full Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition
title_fullStr Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition
title_full_unstemmed Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition
title_short Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition
title_sort alanine mutagenesis in the complementarity determining region 3 of the mtb and hiv-1 peptide-bispecific t cell receptor beta chain affects ligand recognition
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561015/
https://www.ncbi.nlm.nih.gov/pubmed/28861087
http://dx.doi.org/10.3389/fimmu.2017.00983
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