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CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains

CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains
CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains
Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells.
0027-8424
E10956-E10964
Chancellor, Andrew
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Tocheva, Anna
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Cave-Ayland, Christopher
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Tezera, Liku Bekele
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White, Andrew
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Al Dulayymi, Juma'a
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Bridgeman, John
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Tews, Ivo
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Wilson, Susan
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Lissin, Nikolai
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Tebruegge, Marc
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Marshall, Benjamin
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Sharpe, Sally
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Elliott, Timothy
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Skylaris, Chris-Kriton
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Essex, Jonathan W.
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Baird, Mark
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Gadola, Stephan D.
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Elkington, Paul
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Mansour, Salah
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Chancellor, Andrew
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Tocheva, Anna
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Cave-Ayland, Christopher
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Tezera, Liku Bekele
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White, Andrew
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Al Dulayymi, Juma'a
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Bridgeman, John
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Tews, Ivo
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Wilson, Susan
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Lissin, Nikolai
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Tebruegge, Marc
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Marshall, Benjamin
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Sharpe, Sally
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Elliott, Timothy
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Skylaris, Chris-Kriton
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Essex, Jonathan W.
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Baird, Mark
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Gadola, Stephan D.
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Elkington, Paul
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Mansour, Salah
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Chancellor, Andrew, Tocheva, Anna, Cave-Ayland, Christopher, Tezera, Liku Bekele, White, Andrew, Al Dulayymi, Juma'a, Bridgeman, John, Tews, Ivo, Wilson, Susan, Lissin, Nikolai, Tebruegge, Marc, Marshall, Benjamin, Sharpe, Sally, Elliott, Timothy, Skylaris, Chris-Kriton, Essex, Jonathan W., Baird, Mark, Gadola, Stephan D., Elkington, Paul and Mansour, Salah (2017) CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains. Proceedings of the National Academy of Sciences, 114 (51), E10956-E10964. (doi:10.1073/pnas.1708252114).

Record type: Article

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells.

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Accepted/In Press date: 23 October 2017
e-pub ahead of print date: 20 November 2017
Published date: 19 December 2017

Identifiers

Local EPrints ID: 415231
URI: https://eprints.soton.ac.uk/id/eprint/415231
ISSN: 0027-8424
PURE UUID: 15931401-3a8d-44ca-bac8-3823d1445a82
ORCID for Christopher Cave-Ayland: ORCID iD orcid.org/0000-0003-0942-8030
ORCID for Liku Bekele Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for Ivo Tews: ORCID iD orcid.org/0000-0002-4704-1139
ORCID for Timothy Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Chris-Kriton Skylaris: ORCID iD orcid.org/0000-0003-0258-3433
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X

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Date deposited: 03 Nov 2017 17:30
Last modified: 14 Mar 2019 05:29

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Contributors

Author: Andrew Chancellor
Author: Anna Tocheva
Author: Christopher Cave-Ayland ORCID iD
Author: Andrew White
Author: Juma'a Al Dulayymi
Author: John Bridgeman
Author: Ivo Tews ORCID iD
Author: Susan Wilson
Author: Nikolai Lissin
Author: Marc Tebruegge
Author: Sally Sharpe
Author: Timothy Elliott ORCID iD
Author: Mark Baird
Author: Stephan D. Gadola
Author: Paul Elkington ORCID iD
Author: Salah Mansour ORCID iD

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