Alpha-lactosylceramide as a novel "sugar-capped" CD1d ligand for natural killer T cells: biased cytokine profile and therapeutic activities.
The invariant natural killer T cells (iNKT) cells have emerged as an important regulator of immunity to infection, cancer, and autoimmune diseases. They can be activated by glycolipids that bind to CD1d. The most effective iNKT ligand reported to date is alpha-galactosylceramide (alpha-GalCer), which stimulates iNKT cells to secrete both Th-1 and Th-2 cytokines. Indiscriminate induction of both types of cytokines could limit the therapeutic potential of iNKT ligands, as Th-1 and Th-2 cytokines play different roles under physiological and pathological conditions. Therefore, a ligand with a biased cytokine-release profile would be highly desirable. Here, we report the synthesis and biological activity of alpha-lactosylceramide (alpha-LacCer). Our data demonstrate that alpha-LacCer can stimulate iNKT cells to proliferate and release cytokines, both in vitro and in vivo. Interestingly, while alpha-LacCer is approximately 1000-times less efficient than alpha-GalCer in inducing Th-1 cytokines, it is as potent as alpha-GalCer in the induction of Th-2 cytokines; therefore, alpha-LacCer is a novel compound that induces a biased cytokine release. Processing by beta-glycosidase was critical for alpha-LacCer activity. Moreover, in vivo experiments suggest that alpha-LacCer is at least as potent as alpha-GalCer in the treatment of tumors and experimental autoimmune encephalomyelitis.
Zhang
Wenpeng
W
Department of Biochemistry, The Ohio State University, 876 Biological Sciences Building, 484 W12th Avenue, Columbus, OH, 43210, USA.
Zheng
Xincheng
X
Xia
Chengfeng
C
Perali
Ramu Sridhar
RS
Yao
Qingjia
Q
Liu
Yang
Y
Zheng
Pan
P
Wang
Peng George
PG
D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism*; D055610:Antigens, CD1d; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D015195:Drug Design; D007700:Kinetics; D007790:Lactosylceramides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
D018949:Antigens, CD1; D055610:Antigens, CD1d; D000970:Antineoplastic Agents; D016207:Cytokines; D007790:Lactosylceramides; D008024:Ligands; D001616:beta-Galactosidase