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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.

Original publication

DOI

10.1073/pnas.1708252114

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

12/2017

Volume

114

Pages

E10956 - E10964

Addresses

Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.

Keywords

T-Lymphocytes, Humans, Mycobacterium tuberculosis, Tuberculosis, Granuloma, Mycolic Acids, Receptors, Antigen, T-Cell, Antigens, CD1, Antigens, Bacterial, Immunohistochemistry, Lymphocyte Activation, Gene Expression, Molecular Conformation, Protein Binding, Models, Molecular