RESUMEN
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.
Asunto(s)
Antígenos CD1/inmunología , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/metabolismo , Ácidos Micólicos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Tuberculosis/inmunología , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/metabolismo , Antígenos CD1/química , Antígenos CD1/genética , Expresión Génica , Granuloma/inmunología , Granuloma/metabolismo , Granuloma/microbiología , Granuloma/patología , Humanos , Inmunohistoquímica , Activación de Linfocitos/inmunología , Modelos Moleculares , Conformación Molecular , Ácidos Micólicos/química , Ácidos Micólicos/metabolismo , Unión Proteica , Receptores de Antígenos de Linfocitos T/metabolismo , Tuberculosis/microbiologíaRESUMEN
An efficient synthetic approach to tri-arabino di-mycolates, using structurally defined synthetic α-, keto and methoxy mycolic acids is described.