Attenuation of invariant Natural Killer T-cell anergy induction through intradermal delivery of alpha-galactosylceramide

CD1d restricted, α-galactosylceramide (αGC) responsive invariant (i)NKT cells positively regulate immune responses. Both intravenous and intradermal administered αGC are known to activate iNKT cells. iNKT cells become unresponsive to a second intravenous αGC injection, whereas no data are available regarding potential anergy upon intradermal administration. Here, comparative analysis of two intradermal versus two intravenous injections in mice demonstrated that iNKT cell anergy was prevented by intradermal injection and when combined with a vaccine, superior tumor protection afforded by intradermally administered αGC. Moreover, human skin dendritic cells (DC) took up intradermally injected αGC and activated iNKT cells upon migration, while iNKT cells in human skin-draining lymph nodes expanded in response to αGC presented either by exogenously added DC or by CD1d positive antigen presenting cells in the lymph nodes. In conclusion, glycolipids such as αGC may greatly improve the efficacy of skin immunization strategies, targeting cutaneous and lymph node DC.