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).
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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