title: Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells.
abstract: Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; sgadola@gmail.com s.mansour@soton.ac.uk.
authors.forename: Salah
authors.initials: S
authors.lastname: Mansour
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Anna S
authors.initials: AS
authors.lastname: Tocheva
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Chris
authors.initials: C
authors.lastname: Cave-Ayland
authors.affiliation: Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Moritz M
authors.initials: MM
authors.lastname: Machelett
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Barbara
authors.initials: B
authors.lastname: Sander
authors.affiliation: Immunocore Limited, Abingdon, Oxon OX14 4RY, United Kingdom;
authors.forename: Nikolai M
authors.initials: NM
authors.lastname: Lissin
authors.affiliation: Immunocore Limited, Abingdon, Oxon OX14 4RY, United Kingdom;
authors.forename: Peter E
authors.initials: PE
authors.lastname: Molloy
authors.affiliation: School of Chemistry, Bangor University, Bangor, Gwynedd LL57 2DG, United Kingdom;
authors.forename: Mark S
authors.initials: MS
authors.lastname: Baird
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, 17489 Greifswald, Germany;
authors.forename: Gunthard
authors.initials: G
authors.lastname: Stübs
authors.affiliation: Institute for Pathology, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany;
authors.forename: Nicolas W J
authors.initials: NW
authors.lastname: Schröder
authors.affiliation: Institute for Microbiology and Hygiene, Charité University Medical Center, 10117 Berlin, Germany;
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.affiliation: Division of Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany;
authors.forename: Jörg
authors.initials: J
authors.lastname: Rademann
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Postle
authors.affiliation: Immunocore Limited, Abingdon, Oxon OX14 4RY, United Kingdom;
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Ben G
authors.initials: BG
authors.lastname: Marshall
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Rajendra
authors.initials: R
authors.lastname: Gosain
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.affiliation: Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.affiliation: Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Chris-Kriton
authors.initials: CK
authors.lastname: Skylaris
authors.affiliation: Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Essex
authors.affiliation: Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Ivo
authors.initials: I
authors.lastname: Tews
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; Novartis Institutes of Biomedical Research, 4058 Basel, Switzerland sgadola@gmail.com s.mansour@soton.ac.uk.
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Gadola
mesh_terms: D018949:Antigens, CD1 / Q000737:chemistry / Q000276:immunology*; D055610:Antigens, CD1d; D002788:Cholesterol Esters / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C437944:CD1C protein, human; D002788:Cholesterol Esters; D006023:Glycoproteins
keywords: CD1; T cell; antigen presentation; cholesteryl ester; lipid antigen