Modulation of CD1d-Restricted NKT Cell Responses by Using N-Acyl Variants of α-Galactosylceramides

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-03, Vol.102 (9), p.3383-3388
• Main Authors: Karl O. A. Yu, Im, Jin S., Molano, Alberto, Dutronc, Yves, Illarionov, Petr A., Forestier, Claire, Fujiwara, Nagatoshi, Arias, Isa, Miyake, Sachiko, Yamamura, Takashi, Chang, Young-Tae, Besra, Gurdyal S., Porcelli, Steven A., Fearon, Douglas T.
• Format: Article
• Language: English
• Subjects: Animals; Antigen presenting cells; Autoimmune diseases; Biological Sciences; Cytokines; Dose response relationship; Fatty acids; Flow Cytometry; Galactosylceramides - pharmacology; Glycolipids; Hybridomas; Immunology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural killer cells; Natural killer T cells; Splenocytes; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0407488102

A form of α-galactosylceramide, KRN7000, activates CD1d-restricted Vα14-invariant (Vα14i) natural killer (NK) T cells and initiates multiple downstream immune reactions. We report that substituting the C26:0 N-acyl chain of KRN7000 with shorter, unsaturated fatty acids modifies the outcome of Vα14i NKT cell activation. One analogue containing a diunsaturated C20 fatty acid (C20:2) potently induced a T helper type 2-biased cytokine response, with diminished IFN-γ production and reduced Vα14i NKT cell expansion. C20:2 also exhibited less stringent requirements for loading onto CD1d than KRN7000, suggesting a mechanism for the immunomodulatory properties of this lipid. The differential cellular response elicited by this class of Vα14i NKT cell agonists may prove to be useful in immunotherapeutic applications.