Design of soluble recombinant T cell receptors for antigen targeting and T cell inhibition.
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 alphabeta 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 microm 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.
Laugel
Bruno
B
The T-cell Modulation Group, The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Rd., Oxford OX1 3SY, United Kingdom.
Boulter
Jonathan M
JM
Lissin
Nikolai
N
Vuidepot
Annelise
A
Li
Yi
Y
Gostick
Emma
E
Crotty
Laura E
LE
Douek
Daniel C
DC
Hemelaar
Joris
J
Price
David A
DA
Jakobsen
Bent K
BK
Sewell
Andrew K
AK
D000941:Antigens / Q000276:immunology*; D003429:Cross Reactions; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins