title: A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC.
abstract: Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-α chain with the MHC class II β chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3β loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3α loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Dhruv K
authors.initials: DK
authors.lastname: Sethi
authors.forename: David A
authors.initials: DA
authors.lastname: Schubert
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Anders
authors.forename: Annie
authors.initials: A
authors.lastname: Heroux
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bonsor
authors.forename: Chantz P
authors.initials: CP
authors.lastname: Thomas
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sundberg
authors.forename: Jason
authors.initials: J
authors.lastname: Pyrdol
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
mesh_terms: D000818:Animals; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D040681:Structural Homology, Protein
chemical_list: D006649:Histocompatibility Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell