CD1c presentation of synthetic glycolipid antigens with foreign alkyl branching motifs |
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Authors: | de Jong Annemieke Arce Eva Casas Cheng Tan-Yun van Summeren Ruben P Feringa Ben L Dudkin Vadim Crich David Matsunaga Isamu Minnaard Adriaan J Moody D Branch |
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Affiliation: | Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Smith Building Room 538, One Jimmy Fund Way, Boston, MA 02115, USA. |
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Abstract: | Human CD1c is a protein that activates alphabeta 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-beta1-phosphomycoketides and synthetic analogs with either stereorandom or stereospecific methyl branching patterns. T cell responses required both a phosphate and a beta-linked mannose unit, and they showed preference for C(30-34) 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. |
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