樹状細胞を介するinvariant natural killer T 細胞の寛容誘導

抄録

Invariant natural killer T cells (iNKT cells) are a subset of αβ T cell receptor (TCR) positive T cells and express Vα 14 (mouse) or Vα24 TCR (human). iNKT cells recognize lipid antigen, such as α-galactosylceramide (αGC) loaded on CD1d, which is non-classical major histocompatibility complex (MHC) class I-like molecule, and rapidly produce a huge amount of cytokines after stimulation. Although CD1d molecules were expressed on various cell types, dendritic cells (DCs) most efficiently presented αGC to iNKT cells both in vitro and in vivo. Through the antigen-presentation, DCs and iNKT cells reciprocally activated each other. Interestingly, although iNKT cells received both TCR and co-stimulatory stimuli from DCs, they became unresponsive to secondary stimulation (anergy). When restimulated in the prensene of exogenous IL-2, anergized iNKT cells produced IL-4 comparable to control cells but not IFN-γ. After primary stimulation, programmed death-1 (PD-1) molecules were expressed at high level on iNKT cells for certain period. However, αGCactivated iNKT cells in PD-1 deficient mice became anergic as in normal mice. Furthermore, anti-PD-1 blocking mAb was unable to restore their responsiveness. When iNKT cells were stimulated with immobilized anti-CD3 mAb in the presence or absence of anti-CD28 mAb, they produced cytokines in a dose-dependent manner. Unlike in conventional naïve CD4 T cells, the strong TCR-mediated signaling with co-stimulation rendered iNKT cells anergic to the subsequent stimulation with αGC and spleen DCs. Consistent with in vitro assay, the injection of αGC-pulsed DCs was more potent in inducing anergy than B cells. These results indicate that strong TCR-mediated activation with co-stimulation provides signals induces the anergic state in iNKT cells.