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J. Biol. Chem., Vol. 280, Issue 3, 1882-1892, January 21, 2005

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Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition^*

Bruno Laugel, Jonathan M. Boulter, Nikolai Lissin¶, Annelise Vuidepot¶, Yi Li¶, Emma Gostick, Laura E. Crotty||, Daniel C. Douek||, Joris Hemelaar**, David A. Price||, Bent K. Jakobsen¶, and Andrew K. Sewell

From the The T-cell Modulation Group, The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Rd., Oxford OX1 3SY, United Kingdom, Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom, ^¶Avidex Ltd., 57 Milton Park, Abingdon, Oxon OX14 4RX, United Kingdom, ^||Human Immunology Section, Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and ^**Magdalen College, University of Oxford, Oxford OX1 4AU, United Kingdom

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 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 Tax^11–19 epitope bound to HLA A2-HuD^87–95 (K_D 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 (K_D 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.

Received for publication, August 17, 2004 , and in revised form, November 1, 2004.

^* This work was funded by the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1–5.

A Medical Research Council Clinician Scientist.

A Wellcome Trust Senior Fellow. To whom correspondence should be addressed. Tel.: 44-1865-281539; Fax: 44-1865-281530; E-mail: andy.sewell{at}ndm.ox.ac.uk.

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