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Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1266-75. doi: 10.1073/pnas.1519246113. Epub 2016 Feb 16.

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

Author information

1
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.
2
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom;
3
School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
4
Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
5
Immunocore Limited, Abingdon, Oxon OX14 4RY, United Kingdom;
6
School of Chemistry, Bangor University, Bangor, Gwynedd LL57 2DG, United Kingdom;
7
Institute for Community Medicine, University Medicine Greifswald, 17489 Greifswald, Germany;
8
Institute for Pathology, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany;
9
Institute for Microbiology and Hygiene, Charité University Medical Center, 10117 Berlin, Germany;
10
Division of Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany;
11
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;
12
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;
13
Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
14
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.

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.

KEYWORDS:

CD1; T cell; antigen presentation; cholesteryl ester; lipid antigen

PMID:
26884207
PMCID:
PMC4780616
DOI:
10.1073/pnas.1519246113
[Indexed for MEDLINE]
Free PMC Article

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