Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

DOI: 10.1073/pnas.1519246113
PMID: 26884207

Authors: Salah Mansour (University of Southampton) , Anna S. Tocheva (University of Southampton) , Chris Cave- Ayland (University of Southampton) , Moritz M. Machelett (University of Southampton) , Barbara Sander (University of Southampton) , Nikolai M. Lissin (Immunocore Limited) , Peter E. Molloy (Immunocore Limited) , Mark S. Baird (Bangor University) , Gunthard Stübs (University Medicine Greifswald) , Nicolas W. J. Schröder (Otto-von-Guericke University Magdeburg) , Ralf R. Schumann (Charité University Medical Center) , Jörg Rademann (Freie Universität Berlin) , Anthony D. Postle (University of Southampton) , Bent K. Jakobsen (Immunocore Limited) , Ben G. Marshall (University of Southampton) , Rajendra Gosain (University of Southampton) , Paul T. Elkington (University of Southampton) , Tim Elliott (University of Southampton) , Chris- Kriton Skylaris (University of Southampton) , Jonathan W. Essex (University of Southampton) , Ivo Tews (University of Southampton) , Stephan D. Gadola (University of Southampton)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 113 (9)

State: Published (Approved)
Published: February 2016

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.

Journal Keywords: CD1; lipid antigen; antigen presentation; T cell; cholesteryl ester

Subject Areas: Medicine, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography