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

2017; National Academy of Sciences; Volume: 114; Issue: 51 Linguagem: Inglês

10.1073/pnas.1708252114

1091-6490

Andrew Chancellor, Anna S. Tocheva, Chris Cave-Ayland, Liku B. Tezera, Andrew White, Juma’a R. Al Dulayymi, John S. Bridgeman, Ivo Tews, Susan Wilson, Nikolai M. Lissin, Marc Tebruegge, Ben G. Marshall, Sally Sharpe, Tim Elliott, Chris‐Kriton Skylaris, Jonathan W. Essex, Mark S. Baird, Stephan D. Gadola, Paul Elkington, Salah Mansour,

T-cell and B-cell Immunology

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.