Structural Drivers of Antigen Specificity in T Cell Receptors

Antigen specificity is a hallmark of T cell immunity. This specificity is dictated by the T cell receptor (TCR), which recognizes peptide antigens bound and presented by Major Histocompatibility Complex (MHC) proteins using six complementarity determining region (CDR) loops. To understand the molecular basis of specificity, I studied parental and engineered TCRs whose specificity had been switched via molecular evolution along with a clinically relevant TCR that recognizes a non-cognate MHC. I, in conjunction with our collaborators at University of Illinois and Loyola University, combined structural and functional analysis with deep mutational scanning to gain insight into the encoding of TCR specificity. Our findings showed that for TCRs with engineered antigen specificity, the amino acid substitutions controlled the TCR binding mode and thus the interactions throughout the interface. Overall, our results show that the positions on the CDR loops associated with antigen specificity are broadly distributed among the germline and hypervariable loops, and include interactions with both the peptide and MHC protein, with significant implication for engineering TCRs with novel binding properties.