Using an in vitro evolution technique, researchers at the University of Chicago (Chicago, IL) and the University of Illinois (Urbana, IL) have developed T-cell receptor (TCR) proteins with an extremely high affinity for a target peptide–MHC ligand. Besides demonstrating that there is no intrinsic structural block to generating high-affinity TCRs, the findings could have implications for a variety of clinical applications. The approach, described in Proc. Natl. Acad. Sci. USA (97, 5387–5392, 2000), relies on the surface expression and display of mutant single-chain TCRs in a library of yeast cells. By selecting TCRs that bound to a model nine-residue antigen (QL9) from this pool, the researchers were able to avoid the selective pressures that appear to limit TCR affinity in vivo. The team was able to isolate TCRs with an affinity for QL9–MHC 100-fold higher than naturally occurring TCRs. A soluble form of the high-affinity TCR can detect peptide–MHC complexes on antigen-presenting cells, suggesting that the artificially generated TCRs could target these complexes therapeutically. “I see no reason why one couldn't perform immunohistology with these reagents in the same way one does with monoclonal antibodies,” says David Kranz, senior author on the paper.