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Edited by Philippa Marrack, National Jewish Health, Denver, CO, and approved October 23, 2017 (received for review June 9, 2017)
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.
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.
Mtb lipid tails modulate CD1b-mediated immunity
Article Classifications
- Biological Sciences
- Immunology and Inflammation
- Physical Sciences
- Chemistry
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