Skip to main content

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home
  • Log in
  • My Cart

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
Research Article

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

Andrew Chancellor, Anna S. Tocheva, Chris Cave-Ayland, Liku Tezera, Andrew White, Juma’a R. Al Dulayymi, John S. Bridgeman, Ivo Tews, Susan Wilson, Nikolai M. Lissin, Marc Tebruegge, Ben Marshall, Sally Sharpe, Tim Elliott, Chris-Kriton Skylaris, Jonathan W. Essex, Mark S. Baird, Stephan Gadola, Paul Elkington, and Salah Mansour
  1. aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
  2. bPublic Health England, National Infections Service, Porton Down, Salisbury SP4 0JQ, United Kingdom;
  3. cSchool of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  4. dSchool of Chemistry, Bangor University, Bangor, Gwynedd LL57 2UW, United Kingdom;
  5. eCellular Therapeutics Ltd, Manchester M13 9XX, United Kingdom;
  6. fSchool of Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  7. gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  8. hHistochemistry Unit, University of Southampton, Southampton SO16 6YD, United Kingdom;
  9. iImmunocore Ltd., Abingdon, Oxon OX14 4RY, United Kingdom;
  10. jNIHR Southampton Biomedical Research Centre, Southampton SO17 1BJ, United Kingdom;
  11. kGlobal Health Research Institute, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  12. lDepartment of Paediatrics, Faculty of Medicine, University of Melbourne, 3052 Parkville, Australia;
  13. mDepartment of Paediatric Infectious Diseases & Immunology, Evelina London Children’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London SE1 7EH, United Kingdom;
  14. nCancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
  15. oF. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland

See allHide authors and affiliations

PNAS December 19, 2017 114 (51) E10956-E10964; first published November 20, 2017; https://doi.org/10.1073/pnas.1708252114
Andrew Chancellor
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
bPublic Health England, National Infections Service, Porton Down, Salisbury SP4 0JQ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anna S. Tocheva
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chris Cave-Ayland
cSchool of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Liku Tezera
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew White
bPublic Health England, National Infections Service, Porton Down, Salisbury SP4 0JQ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Juma’a R. Al Dulayymi
dSchool of Chemistry, Bangor University, Bangor, Gwynedd LL57 2UW, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John S. Bridgeman
eCellular Therapeutics Ltd, Manchester M13 9XX, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ivo Tews
fSchool of Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susan Wilson
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
hHistochemistry Unit, University of Southampton, Southampton SO16 6YD, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nikolai M. Lissin
iImmunocore Ltd., Abingdon, Oxon OX14 4RY, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marc Tebruegge
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
jNIHR Southampton Biomedical Research Centre, Southampton SO17 1BJ, United Kingdom;
kGlobal Health Research Institute, University of Southampton, Southampton SO17 1BJ, United Kingdom;
lDepartment of Paediatrics, Faculty of Medicine, University of Melbourne, 3052 Parkville, Australia;
mDepartment of Paediatric Infectious Diseases & Immunology, Evelina London Children’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London SE1 7EH, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ben Marshall
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
jNIHR Southampton Biomedical Research Centre, Southampton SO17 1BJ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sally Sharpe
bPublic Health England, National Infections Service, Porton Down, Salisbury SP4 0JQ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tim Elliott
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
nCancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chris-Kriton Skylaris
cSchool of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan W. Essex
cSchool of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom;
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark S. Baird
dSchool of Chemistry, Bangor University, Bangor, Gwynedd LL57 2UW, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephan Gadola
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
oF. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Elkington
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
jNIHR Southampton Biomedical Research Centre, Southampton SO17 1BJ, United Kingdom;
kGlobal Health Research Institute, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Salah Mansour
aAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
gInstitute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: s.mansour@soton.ac.uk
  1. Edited by Philippa Marrack, National Jewish Health, Denver, CO, and approved October 23, 2017 (received for review June 9, 2017)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

Significance

Tuberculosis is a major global pandemic responsible for more deaths than any other infectious disease, yet no effective vaccine exists. Here, we demonstrate CD1b expression within human tuberculous granulomas, supporting a role for CD1b lipid antigen presentation in host immunity to infection. CD1b presents mycolates, the dominant Mycobacterium tuberculosis (Mtb) cell wall lipid class and key virulence factors, to αβ T cells. We reveal that mycolate tail moieties, distal to the head group, are antigenic determinants for the conserved human germline-encoded mycolyl lipid-reactive (GEM) T cell receptors (TCRs). Computational simulations suggest a putative mechanism whereby lipid-ligand dynamics within CD1b regulate GEM-TCR activity. This work provides insights for the development of major histocompatibility complex (MHC)-independent Mtb lipid vaccines, including those that target GEM T cells.

Abstract

Tuberculosis (TB), 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 TB 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.

  • Mycobacterium tuberculosis
  • GEM T cells
  • CD1b
  • mycolate lipids
  • molecular dynamics

Footnotes

  • ↵1Present address: Department of Medicine, New York University School of Medicine, New York, NY 10016.

  • ↵2To whom correspondence should be addressed. Email: s.mansour{at}soton.ac.uk.
  • Author contributions: A.C., S.G., and S.M. designed research; A.C., A.S.T., C.C.-A., L.T., A.W., J.R.A.D., N.M.L., T.E., C.-K.S., J.W.E., P.E., and S.M. performed research; J.R.A.D., J.S.B., S.W., N.M.L., M.T., B.M., M.S.B., and P.E. contributed new reagents/analytic tools; A.C., C.C.-A., L.T., A.W., J.S.B., I.T., S.W., M.T., B.M., S.S., T.E., C.-K.S., J.W.E., M.S.B., S.G., P.E., and S.M. analyzed data; and A.C. and S.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • See Commentary on page 13312.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1708252114/-/DCSupplemental.

Published under the PNAS license.

View Full Text
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Mtb lipid tails modulate CD1b-mediated immunity
Andrew Chancellor, Anna S. Tocheva, Chris Cave-Ayland, Liku Tezera, Andrew White, Juma’a R. Al Dulayymi, John S. Bridgeman, Ivo Tews, Susan Wilson, Nikolai M. Lissin, Marc Tebruegge, Ben Marshall, Sally Sharpe, Tim Elliott, Chris-Kriton Skylaris, Jonathan W. Essex, Mark S. Baird, Stephan Gadola, Paul Elkington, Salah Mansour
Proceedings of the National Academy of Sciences Dec 2017, 114 (51) E10956-E10964; DOI: 10.1073/pnas.1708252114

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Mtb lipid tails modulate CD1b-mediated immunity
Andrew Chancellor, Anna S. Tocheva, Chris Cave-Ayland, Liku Tezera, Andrew White, Juma’a R. Al Dulayymi, John S. Bridgeman, Ivo Tews, Susan Wilson, Nikolai M. Lissin, Marc Tebruegge, Ben Marshall, Sally Sharpe, Tim Elliott, Chris-Kriton Skylaris, Jonathan W. Essex, Mark S. Baird, Stephan Gadola, Paul Elkington, Salah Mansour
Proceedings of the National Academy of Sciences Dec 2017, 114 (51) E10956-E10964; DOI: 10.1073/pnas.1708252114
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley

Article Classifications

  • Biological Sciences
  • Immunology and Inflammation
  • Physical Sciences
  • Chemistry

See related content:

  • Grasping mycobacterial lipid antigens
    - Dec 07, 2017
Proceedings of the National Academy of Sciences: 114 (51)
Table of Contents

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Materials and Methods
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Water from a faucet fills a glass.
News Feature: How “forever chemicals” might impair the immune system
Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
Image credit: Shutterstock/Dmitry Naumov.
Reflection of clouds in the still waters of Mono Lake in California.
Inner Workings: Making headway with the mysteries of life’s origins
Recent experiments and simulations are starting to answer some fundamental questions about how life came to be.
Image credit: Shutterstock/Radoslaw Lecyk.
Cave in coastal Kenya with tree growing in the middle.
Journal Club: Small, sharp blades mark shift from Middle to Later Stone Age in coastal Kenya
Archaeologists have long tried to define the transition between the two time periods.
Image credit: Ceri Shipton.
Mouse fibroblast cells. Electron bifurcation reactions keep mammalian cells alive.
Exploring electron bifurcation
Jonathon Yuly, David Beratan, and Peng Zhang investigate how electron bifurcation reactions work.
Listen
Past PodcastsSubscribe
Panda bear hanging in a tree
How horse manure helps giant pandas tolerate cold
A study finds that giant pandas roll in horse manure to increase their cold tolerance.
Image credit: Fuwen Wei.

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Special Feature Articles – Most Recent
  • List of Issues

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Subscribers
  • Librarians
  • Press
  • Cozzarelli Prize
  • Site Map
  • PNAS Updates
  • FAQs
  • Accessibility Statement
  • Rights & Permissions
  • About
  • Contact

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490