T Cell Receptor Signaling Is Limited by Docking Geometry to Peptide-Major Histocompatibility Complex

Abstract

T cell receptor (TCR) engagement of peptide-major histocompatibility complex (MHC) is essential to adaptive immunity, but it is unknown if TCR signaling responses are influenced by the binding topology of the TCR-peptide-MHC complex. We developed yeast-displayed peptide-MHC libraries that enabled us to identify new peptide sequences reactive with a single TCR. Structural analysis showed that four peptides bound to the TCR with distinct 3-dimensional (3D) and 2D affinities, using entirely different binding chemistries. Three of the peptides that shared a common docking mode, where key TCR-MHC germline interactions are preserved, induced TCR signaling. The fourth peptide failed to induce signaling, and was recognized in a substantially different TCR-MHC binding mode that apparently exceeded geometric tolerances compatible with signaling. We suggest that the ‘stereotypical’ TCR-MHC docking paradigm evolved from productive signaling geometries, and that TCR signaling can be modulated by peptides that are recognized in alternative TCR-pMHC binding orientations.