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

Mansour, Salah, Tocheva, Anna S., Cave-Ayland, Christopher, Machelett, Moritz M., Sander, Barbara, Lissin, Nikolai M., Molloy, Peter E., Baird, Mark S., Stübs, Gunthard, Schröder, Nicolas W.J., Schumann, Ralf R., Rademann, Jörg, Postle, Anthony D., Jakobsen, Bent K., Marshall, Ben G., Gosain, Rajendra, Elkington, Paul T, Elliott, Timothy, Skylaris, Chris-Kriton, Essex, Jonathan W., Tews, Ivo and Gadola, Stephan D. (2016) Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells Proceedings of the National Academy of Sciences, 113, (9), E1266-E1275. (doi:10.1073/pnas.1519246113). (PMID:26884207).


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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.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1073/pnas.1519246113
ISSNs: 0027-8424 (print)
Keywords: cd1, lipid antigen, antigen presentation, t cell, cholesteryl ester
Organisations: Computational Systems Chemistry
ePrint ID: 390565
Date :
Date Event
21 January 2016Accepted/In Press
16 February 2016e-pub ahead of print
Date Deposited: 05 Apr 2016 07:56
Last Modified: 17 Apr 2017 03:49
Further Information:Google Scholar

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