Distinct CDR3 Conformations in T Cell Receptors Determine the Level of Cross-Reactivity for Diverse Antigens, but Not the Docking Orientation

• Published in: The Journal of immunology (1950) 2008-11, Vol.181 (9), p.6255-6264
• Main Authors: Jones, Lindsay L., Colf, Leremy A., Stone, Jennifer D., Garcia, K. Christopher, Kranz, David M.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

T cells are known to cross-react with diverse peptide MHC antigens through their αβ TCRs. To explore the basis of such cross-reactivity, we examined the 2C TCR that recognizes two structurally distinct ligands, SIY-K b and alloantigen QL9-L d . Here we characterized the crossreactivity of several high affinity 2C TCR variants that contained mutations only in the CDR3α loop. Two of the TCRs lost their ability to cross-react with the reciprocal ligand (SIY-K b ), while another TCR (m67) maintained reactivity with both ligands. Crystal structures of four of the TCRs in complex with QL9-L d showed that CDR1, CDR2, and CDR3β conformations and docking orientations were remarkably similar. Although the CDR3α loop of TCR m67 conferred a 2000-fold higher affinity for SIY-K b , the TCR maintained the same docking angle on QL9-L d as the 2C TCR. Thus, CDR3α dictated the affinity and level of cross-reactivity, yet it did so without affecting the conserved docking orientation.