title: The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins.
abstract: Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved αβ T-cell lineage that express a semi-invariant T-cell receptor (TCR) restricted to the MHC related-1 (MR1) protein. MAIT cells are dependent upon MR1 expression and exposure to microbes for their development and stimulation, yet these cells can exhibit microbial-independent stimulation when responding to MR1 from different species. We have used this microbial-independent, cross-species reactivity of MAIT cells to define the molecular basis of MAIT-TCR/MR1 engagement and present here a 2.85 Å complex structure of a human MAIT-TCR bound to bovine MR1. The MR1 binding groove is similar in backbone structure to classical peptide-presenting MHC class I molecules (MHCp), yet is partially occluded by large aromatic residues that form cavities suitable for small ligand presentation. The docking of the MAIT-TCR on MR1 is perpendicular to the MR1 surface and straddles the MR1 α1 and α2 helices, similar to classical αβ TCR engagement of MHCp. However, the MAIT-TCR contacts are dominated by the α-chain, focused on the MR1 α2 helix. TCR β-chain contacts are mostly through the variable CDR3β loop that is positioned proximal to the CDR3α loop directly over the MR1 open groove. The elucidation of the MAIT TCR/MR1 complex structure explains how the semi-invariant MAIT-TCR engages the nonpolymorphic MR1 protein, and sheds light onto ligand discrimination by this cell type. Importantly, this structure also provides a critical link in our understanding of the evolution of αβ T-cell recognition of MHC and MHC-like ligands.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jacinto
authors.initials: J
authors.lastname: López-Sagaseta
authors.forename: Charles L
authors.initials: CL
authors.lastname: Dulberger
authors.forename: James E
authors.initials: JE
authors.lastname: Crooks
authors.forename: Chelsea D
authors.initials: CD
authors.lastname: Parks
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Luoma
authors.forename: Amanda
authors.initials: A
authors.lastname: McFedries
authors.forename: Ildiko
authors.initials: I
authors.lastname: Van Rhijn
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D015778:Minor Histocompatibility Antigens; D062105:Molecular Docking Simulation; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism*
chemical_list: D015395:Histocompatibility Antigens Class I; D008024:Ligands; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins
keywords: antigen-presentation; metabolite; molecular recognition; unconventional T cells