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.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 19 Dec 2017|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Richard Jewell and Carolann McGuire for their assistance with flow cytometry (FACS facility, Faculty of Medicine, University of Southampton), Jenny Norman (Histochemistry Research Unit) for undertaking the immunohistochemical staining, and Sanjay Jogai for providing the reagents for immunohistochemistry. Special thanks to Joseph Sanderson, Andrew Gerry, and Bent Jakobsen for advice and support in generating GEM-TCR–transduced T cell lines. We also thank Liselotte Brix, Andreas Fløe Nielsen, and Bjarke Endel Hansen for generous provision of dextran backbone, CD1b monomers, and support in generating soluble fluorescent dextramers. Many thanks to Akul Singhania for production of the heat map and for statistical support. This work was supported by Public Health England, US NIH Grant R33AI102239, UK Medical Research Council Grant MR/N006631/1, and Cancer Research UK Grant A23562.
- GEM T cells
- Molecular dynamics
- Mycobacterium tuberculosis
- Mycolate lipids