MHC class I downregulation represents a significant challenge for successful T cell-based immunotherapy. T cell epitopes associated with impaired peptide processing (TEIPP) constitute a novel category of immunogenic Ags that are selectively presented on transporter associated with Ag processing-deficient cells. The TEIPP neoepitopes are CD8 T cell targets， derived from nonmutated self-proteins that might be exploited to prevent immune escape. In this study， the crystal structure of H-2D(b) in complex with the first identified TEIPP Ag (MCLRMTAVM) derived from the Trh4 protein has been determined to 2.25 Å resolution. In contrast to prototypic H-2D(b) peptides， Trh4 takes a noncanonical peptide-binding pa... More
MHC class I downregulation represents a significant challenge for successful T cell-based immunotherapy. T cell epitopes associated with impaired peptide processing (TEIPP) constitute a novel category of immunogenic Ags that are selectively presented on transporter associated with Ag processing-deficient cells. The TEIPP neoepitopes are CD8 T cell targets， derived from nonmutated self-proteins that might be exploited to prevent immune escape. In this study， the crystal structure of H-2D(b) in complex with the first identified TEIPP Ag (MCLRMTAVM) derived from the Trh4 protein has been determined to 2.25 Å resolution. In contrast to prototypic H-2D(b) peptides， Trh4 takes a noncanonical peptide-binding pattern with extensive sulfur-π interactions that contribute to the overall complex stability. Importantly， the noncanonical methionine at peptide position 5 acts as a main anchor， altering only the conformation of the H-2D(b) residues Y156 and H155 and thereby forming a unique MHC/peptide conformer that is essential for recognition by TEIPP-specific T cells. Substitution of peptide residues p2C and p5M to the conservative α-aminobutyric acid and norleucine， respectively， significantly reduced complex stability， without altering peptide conformation or T cell recognition. In contrast， substitution of p5M to a conventional asparagine abolished recognition by the H-2D(b)/Trh4-specific T cell clone LnB5. We anticipate that the H-2D(b)/Trh4 complex represents the first example， to our knowledge， of a broader repertoire of alternative MHC class I binders.
