The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer

The Journal of Immunology : Official Journal of the American Association of Immunologists
Ida HafstrandAdnane Achour

Abstract

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 p...Continue Reading

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Citations

Mar 7, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ida HafstrandAdnane Achour
Dec 14, 2018·Pharmacological Reviews·Feixiong ChengRuth Nussinov
Feb 28, 2019·Proceedings of the National Academy of Sciences of the United States of America·Ida HafstrandAdnane Achour
Oct 26, 2018·Cancer Immunology Research·Eleanor Clancy-ThompsonStephanie K Dougan

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