Fluorine substitutions in an antigenic peptide selectively modulate T cell receptor binding in a minimally perturbing manner

Authors

Kurt H. Piepenbrink, University of Notre DameFollow
Oleg Y. Borbulevych, University of Notre Dame
Ruth F. Sommese, University of Notre Dame
John Clemens, University of Notre Dame
Kathrynq M. Armstrong, University of Notre Dame
Clare Desmond, University of Notre Dame
Priscilla Do, University of Notre Dame
Brian M. Baker, University of Notre Dame

Date of this Version

1-4-2011

Document Type

Article

Citation

Biochem J. ; 423(3): 353–361. doi:10.1042/BJ20090732

Abstract

T cell receptor (TCR) recognition of antigenic peptides bound and presented by major histocompatibility complex (MHC) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide/MHC molecules weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Further, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. Here, we studied how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we found that fluorination of the HTLV-1 Tax11-19 peptide (Tax) enhanced binding by the Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The changes in affinity were consistent with crystallographic structures and fluorine chemistry, and with A6, independent of other substitutions in the interface. Peptide fluorination thus provides a means to selectively modulate TCR binding affinity without significantly perturbing peptide composition or structure. Lastly, in probing the mechanism of fluorine’s effect on TCR binding, our data were most consistent with fluorine’s unique “polar hydrophobicity,” a finding which should impact other attempts to alter molecular recognition with fluorine.