Design of soluble recombinant T Cell receptors for antigen targeting and T cell inhibition

Laugel, B., Boulter, J. M., Lissin, N., Vuidepot, A., Gostick, E., Crotty, L. E., Douek, D. C., Hemelaar, J., Price, David ORCID: https://orcid.org/0000-0001-9416-2737, Jakobsen, B. and Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 2005. Design of soluble recombinant T Cell receptors for antigen targeting and T cell inhibition. Journal of Biological Chemistry 280 (3) , pp. 1882-1892. 10.1074/jbc.M409427200

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Abstract

The use of recombinant T cell receptors (TCRs) to target therapeutic interventions has been hindered by the naturally low affinity of TCR interactions with peptide major histocompatibility complex ligands. Here, we use multimeric forms of soluble heterodimeric αβ TCRs for specific detection of target cells pulsed with cognate peptide, discrimination of quantitative changes in antigen display at the cell surface, identification of virus-infected cells, inhibition of antigen-specific cytotoxic T lymphocyte activation, and identification of cross-reactive peptides. Notably, the A6 TCR specific for the immunodominant HLA A2-restricted human T cell leukemia virus type 1 Tax11–19 epitope bound to HLA A2-HuD87–95 (KD 120 μM by surface plasmon resonance), an epitope implicated as a causal antigen in the paraneoplastic neurological degenerative disorder anti-Hu syndrome. A mutant A6 TCR that exhibited dramatically increased affinity for cognate antigen (KD 2.5 nM) without enhanced cross-reactivity was generated; this TCR demonstrated potent biological activity even as a monomeric molecule. These data provide insights into TCR repertoire selection and delineate a framework for the selective modification of TCRs in vitro that could enable specific therapeutic intervention in vivo.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Date of First Compliant Deposit:	5 May 2016
Last Modified:	01 Nov 2022 10:09
URI:	https://orca.cardiff.ac.uk/id/eprint/90452

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