title: The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer.
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 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.
authors.affiliation: Science for Life Laboratory, Department of Medicine, Solna, Karolinska Institutet, SE-10450 Stockholm, Sweden; and.
authors.forename: Ida
authors.initials: I
authors.lastname: Hafstrand
authors.affiliation: Clinical Oncology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
authors.forename: Elien M
authors.initials: EM
authors.lastname: Doorduijn
authors.affiliation: Science for Life Laboratory, Department of Medicine, Solna, Karolinska Institutet, SE-10450 Stockholm, Sweden; and.
authors.forename: Adil Doganay
authors.initials: AD
authors.lastname: Duru
authors.affiliation: Science for Life Laboratory, Department of Medicine, Solna, Karolinska Institutet, SE-10450 Stockholm, Sweden; and.
authors.forename: Jeremie
authors.identifier: http://orcid.org/0000-0002-6730-336X
authors.initials: J
authors.lastname: Buratto
authors.affiliation: Clinical Oncology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
authors.forename: Claudia Cunha
authors.initials: CC
authors.lastname: Oliveira
authors.affiliation: Science for Life Laboratory, Department of Medicine, Solna, Karolinska Institutet, SE-10450 Stockholm, Sweden; and.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sandalova
authors.affiliation: Clinical Oncology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands adnane.achour@ki.se T.van_Hall@lumc.nl.
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.affiliation: Science for Life Laboratory, Department of Medicine, Solna, Karolinska Institutet, SE-10450 Stockholm, Sweden; and adnane.achour@ki.se T.van_Hall@lumc.nl.
authors.forename: Adnane
authors.identifier: http://orcid.org/0000-0003-0432-710X
authors.initials: A
authors.lastname: Achour
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D / Q000276:immunology / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D018984:Epitopes, T-Lymphocyte; D064532:Histocompatibility Antigen H-2D; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; C479747:Trh4 protein, mouse