Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 10, Pages 5387-5392Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.080078297
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- NIGMS NIH HHS [R01 GM055767, R01 GM55767] Funding Source: Medline
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T cell receptors (TCRs) exhibit genetic and structural diversity similar to antibodies, but they have binding affinities that are several orders of magnitude lower. It has been suggested that TCRs undergo selection in vivo to maintain lower affinities. Here, we show that there is not an inherent genetic or structural limitation on higher affinity. Higher-affinity TCR Variants were generated in the absence of in vivo selective pressures by using yeast display and selection from a library of V alpha CDR3 mutants. Selected mutants had greater than 100-fold higher affinity (K-D approximate to 9 nM) for the peptide/MHC ligand while retaining a high degree of peptide specificity. Among the high-affinity TCR mutants, a strong preference was found for CDP3 alpha that contained Pro or Cry residues. Finally, unlike the wild-type TCR, a soluble monomeric form of a high-affinity TCR was capable of directly detecting peptide/MHC complexes on antigen-presenting cells. These findings prove that affinity maturation of TCRs is possible and suggest a strategy for engineering TCRs that can be used in targeting specific peptide/MHC complexes for diagnostic: and therapeutic purposes.
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