Molecular design of the Calphabeta interface favors specific pairing of introduced TCRalphabeta in human T cells.

Détails

ID Serval
serval:BIB_39B6C7CF9E09
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Molecular design of the Calphabeta interface favors specific pairing of introduced TCRalphabeta in human T cells.
Périodique
Journal of Immunology
Auteur⸱e⸱s
Voss R.H., Willemsen R.A., Kuball J., Grabowski M., Engel R., Intan R.S., Guillaume P., Romero P., Huber C., Theobald M.
ISSN
0022-1767 (Print)
ISSN-L
0022-1767
Statut éditorial
Publié
Date de publication
2008
Volume
180
Numéro
1
Pages
391-401
Langue
anglais
Résumé
A promising approach to adoptive transfer therapy of tumors is to reprogram autologous T lymphocytes by TCR gene transfer of defined Ag specificity. An obstacle, however, is the undesired pairing of introduced TCRalpha- and TCRbeta-chains with the endogenous TCR chains. These events vary depending on the individual endogenous TCR and they not only may reduce the levels of cell surface-introduced TCR but also may generate hybrid TCR with unknown Ag specificities. We show that such hybrid heterodimers can be generated even by the pairing of human and mouse TCRalpha- and TCRbeta-chains. To overcome this hurdle, we have identified a pair of amino acid residues in the crystal structure of a TCR that lie at the interface of associated TCR Calpha and Cbeta domains and are related to each other by both a complementary steric interaction analogous to a "knob-into-hole" configuration and the electrostatic environment. We mutated the two residues so as to invert the sense of this interaction analogous to a charged "hole-into-knob" configuration. We show that this inversion in the CalphaCbeta interface promotes selective assembly of the introduced TCR while preserving its specificity and avidity for Ag ligand. Noteworthily, this TCR modification was equally efficient on both a Mu and a Hu TCR. Our data suggest that this approach is generally applicable to TCR independently of their Ag specificity and affinity, subset distribution, and species of origin. Thus, this strategy may optimize TCR gene transfer to efficiently and safely reprogram random T cells into tumor-reactive T cells.
Mots-clé
Animals, Cell Membrane/metabolism, Crystallography, X-Ray, Dimerization, Gene Transfer Techniques, Humans, Mice, Point Mutation, Protein Conformation, Protein Transport, Receptors, Antigen, T-Cell, alpha-beta/chemistry, Receptors, Antigen, T-Cell, alpha-beta/genetics, T-Lymphocytes/immunology
Pubmed
Web of science
Création de la notice
18/01/2011 10:08
Dernière modification de la notice
20/08/2019 14:29
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