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

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells
Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells
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.
cd1, lipid antigen, antigen presentation, t cell, cholesteryl ester
0027-8424
E1266-E1275
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Tocheva, Anna S.
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Cave-Ayland, Christopher
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Machelett, Moritz M.
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Sander, Barbara
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Lissin, Nikolai M.
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Molloy, Peter E.
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Baird, Mark S.
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Stübs, Gunthard
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Schröder, Nicolas W.J.
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Schumann, Ralf R.
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Rademann, Jörg
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Postle, Anthony D.
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Jakobsen, Bent K.
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Marshall, Ben G.
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Gosain, Rajendra
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Elkington, Paul T
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Elliott, Timothy
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Skylaris, Chris-Kriton
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Essex, Jonathan W.
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Tews, Ivo
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Gadola, Stephan D.
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Mansour, Salah
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Tocheva, Anna S.
f428e2af-7338-4cf3-bb12-9fe37e4fcbb0
Cave-Ayland, Christopher
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Machelett, Moritz M.
c9aa7658-2a08-48d6-9ce1-8c3b6d00a58c
Sander, Barbara
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Lissin, Nikolai M.
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Molloy, Peter E.
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Baird, Mark S.
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Stübs, Gunthard
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Schröder, Nicolas W.J.
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Schumann, Ralf R.
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Rademann, Jörg
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Postle, Anthony D.
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Jakobsen, Bent K.
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Marshall, Ben G.
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Gosain, Rajendra
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Elkington, Paul T
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Elliott, Timothy
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Skylaris, Chris-Kriton
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Essex, Jonathan W.
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Tews, Ivo
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Gadola, Stephan D.
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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. (PMID:26884207).

Record type: Article

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.

PDF Mansour PNAS Revised Manuscript_submission.pdf - Accepted Manuscript
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More information

Accepted/In Press date: 21 January 2016
e-pub ahead of print date: 16 February 2016
Keywords: cd1, lipid antigen, antigen presentation, t cell, cholesteryl ester
Organisations: Computational Systems Chemistry

Identifiers

Local EPrints ID: 390565
URI: http://eprints.soton.ac.uk/id/eprint/390565
ISSN: 0027-8424
PURE UUID: dfa752e4-e70d-44be-aea8-8edbc836b764
ORCID for Anthony D. Postle: ORCID iD orcid.org/0000-0001-7361-0756
ORCID for Paul T Elkington: ORCID iD orcid.org/0000-0003-0390-0613
ORCID for Timothy Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746
ORCID for Ivo Tews: ORCID iD orcid.org/0000-0002-4704-1139

Catalogue record

Date deposited: 05 Apr 2016 07:56
Last modified: 07 Nov 2017 20:23

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Contributors

Author: Salah Mansour
Author: Anna S. Tocheva
Author: Christopher Cave-Ayland
Author: Barbara Sander
Author: Nikolai M. Lissin
Author: Peter E. Molloy
Author: Mark S. Baird
Author: Gunthard Stübs
Author: Nicolas W.J. Schröder
Author: Ralf R. Schumann
Author: Jörg Rademann
Author: Bent K. Jakobsen
Author: Ben G. Marshall
Author: Rajendra Gosain
Author: Timothy Elliott ORCID iD
Author: Ivo Tews ORCID iD
Author: Stephan D. Gadola

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