CD1c presentation of synthetic glycolipid antigens with foreign alkyl branching motifs.
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.
de Jong
Annemieke
A
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.
Arce
Eva Casas
EC
Cheng
Tan-Yun
TY
van Summeren
Ruben P
RP
Feringa
Ben L
BL
Dudkin
Vadim
V
Crich
David
D
Matsunaga
Isamu
I
Minnaard
Adriaan J
AJ
Moody
D Branch
DB
D000941:Antigens / Q000378:metabolism*; D018949:Antigens, CD1 / Q000378:metabolism*; D006017:Glycolipids / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology
D000941:Antigens; D018949:Antigens, CD1; C437944:CD1C protein, human; D006017:Glycolipids; D006023:Glycoproteins