Synthesis of dideoxymycobactin antigens presented by CD1a reveals T cell fine specificity for natural lipopeptide structures.
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 alpha-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.
Young
David C
DC
Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kasmar
Anne
A
Moraski
Garrett
G
Cheng
Tan-Yun
TY
Walz
Andrew J
AJ
Hu
Jingdan
J
Xu
Yanping
Y
Endres
Gregory W
GW
Uzieblo
Adam
A
Zajonc
Dirk
D
Costello
Catherine E
CE
Miller
Marvin J
MJ
Moody
D Branch
DB
D018949:Antigens, CD1 / Q000737:chemistry*; D002087:Butyrates / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D006880:Hydroxy Acids; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D008055:Lipids / Q000737:chemistry; D055666:Lipopeptides / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry*; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000382:microbiology
C482821:3R-hydroxybutyric acid; D018949:Antigens, CD1; D002087:Butyrates; C419393:CD1a antigen; D006880:Hydroxy Acids; D008055:Lipids; D055666:Lipopeptides; D010080:Oxazoles; C018608:mycobactins; D008239:Lysine