Synthesis of Dideoxymycobactin Antigens Presented by CD1a Reveals T Cell Fine Specificity for Natural Lipopeptide Structures

• Published in: The Journal of biological chemistry 2009-09, Vol.284 (37), p.25087-25096
• Main Authors: Young, David C., Kasmar, Anne, Moraski, Garrett, Cheng, Tan-Yun, Walz, Andrew J., Hu, Jingdan, Xu, Yanping, Endres, Gregory W., Uzieblo, Adam, Zajonc, Dirk, Costello, Catherine E., Miller, Marvin J., Moody, D. Branch
• Format: Article
• Language: English
• Subjects: Antigens, CD1 - chemistry; Butyrates - chemistry; Cell survival; Gas Chromatography-Mass Spectrometry - methods; Humans; Hydroxy Acids; Infectious diseases; Leukocytes, Mononuclear - microbiology; Lipids; Lipids - chemistry; Lipids and Lipoproteins: Metabolism, Regulation, and Signaling; lipopeptides; Lipopeptides - chemistry; Lymphocytes T; Lysine - chemistry; Mass spectroscopy; Models, Chemical; Models, Molecular; Mycobacterium tuberculosis; Mycobacterium tuberculosis - metabolism; N.M.R; Oxazoles - chemistry; Peptide synthesis; Serine; Siderophores; Stereochemistry; Stereoisomerism; T-Lymphocytes - metabolism; T-Lymphocytes - microbiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.000802

Mycobacterium tuberculosis survival in cells requires mycobactin siderophores. Recently, the search for lipid antigens presented by the CD1a antigen-presenting protein led to the discovery of a mycobactin-like compound, dideoxymycobactin (DDM). Here we synthesize DDMs using solution phase and solid phase peptide synthesis chemistry. Comparison of synthetic standards to natural mycobacterial mycobactins by nuclear magnetic resonance and mass spectrometry allowed identification of an unexpected α-methyl serine unit in natural DDM. This finding further distinguishes these pre-siderophores as foreign compounds distinct from conventional peptides, and we provide evidence that this chemical variation influences the T cell response. One synthetic DDM recapitulated natural structures and potently stimulated T cells, making it suitable for patient studies of CD1a in infectious disease. DDM analogs differing in the stereochemistry of their butyrate or oxazoline moieties were not recognized by human T cells. Therefore, we conclude that T cells show precise specificity for both arms of the peptide, which are predicted to lie at the CD1a-T cell receptor interface.