CD1c Presentation of Synthetic Glycolipid Antigens with Foreign Alkyl Branching Motifs Original Research Article

Human CD1c is a protein that activates αβ T cells by presenting self antigens, synthetic mannosyl phosphodolichols, and mycobacterial mannosyl phosphopolyketides. To determine which molecular features of antigen structure confer a T cell response, we measured activation by structurally divergent Mycobacterium tuberculosis mannosyl-β1-phosphomycoketides and synthetic analogs with either stereorandom or stereospecific methyl branching patterns. T cell responses required both a phosphate and a β-linked mannose unit, and they showed preference for C30–34 lipid units with methyl branches in the S-configuration. Thus, T cell responses were strongest for synthetic compounds that mimicked the natural branched lipids produced by mycobacterial polyketide synthase 12. Incorporation of methylmalonate to form branched lipids is a common bacterial lipid-synthesis pathway that is absent in vertebrates. Therefore, the preferential recognition of branched lipids may represent a new lipid-based pathogen-associated molecular pattern.