NKT cell ligand alpha-galactosylceramide blocks the induction of oral tolerance by triggering dendritic cell maturation.

NKT cells play contradictory roles in vivo, both regulating autoimmunity and activating immunity to intracellular pathogens and tumors. In this study, we studied the effect of NKT cell activation on the induction of systemic tolerance by oral administration of antigen. Administration of alpha-galactosylceramide (alphaGC) at the time of oral ovalbumin (OVA) feeding completely blocked the OVA-specific tolerance induced by both high- and low-dose regimens in BALB/c mice. In the mesenteric lymph nodes (MLN) of alphaGC-treated mice, the proliferation of OVA-specific T cells was greater than that seen in the MLN of vehicle-treated mice in vivo. The administration of alphaGC triggered the full maturation of mesenteric dendritic cells (DC), which were in turn responsible for the enhanced division of OVA-specific T cells in vitro. To further determine whether the costimulation provided by DC in alphaGC-treated mice was responsible for the reversal of oral tolerance in vivo, mice were given alphaGC together with anti-CD80 and anti-CD86 blocking Ab. OVA-specific systemic tolerance was restored in mice given the blocking Ab, even when they simultaneously received alphaGC. Therefore, oral tolerance can be reversed via costimulation by DC that have been triggered to fully mature by the administration of alphaGC.