A distinct IL-18-induced pathway to fully activate NK T lymphocytes independently from TCR engagement

NK T lymphocytes are characterized by their ability to promptly generate IL -4 and IFN-gamma upon TCR engagement, Here, we demonstrate that these cells can also be fully activated in the absence of TCR cross-linking in respons e to the proinflammatory cytokine IL-18 associated with IL-12. NK T cells s timulated with IL-18 plus IL-12 proliferated, killed Fas(+) target cells, a nd produced high levels of IFN-gamma without IL-4, In these conditions, IFN -gamma production was at least 10-fold higher than that upon TCR cross-link ing. Interestingly, a 2-h pretreatment with IL-12 plus IL-18 sufficed to ma intain the high IFN-gamma-producing potential during subsequent stimulation with anti-TCR mAbs or with the specific Ag alpha-galactosylceramide. Simil ar effects were observed in vivo, because splenic CD4(+) NK T cells from MH C class II-deficient mice secreted IFN-gamma without further stimulation wh en removed 2 h after a single injection of IL-12 plus IL-18, In conclusion, our evidence for activation of NK T lymphocytes in response to IL-18 plus IL-12 in the absence of TCR engagement together with the maintenance of pre ferential IFN-gamma vs IL-4 production upon subsequent exposure to specific Ags is consistent with the active participation of this cell population in innate as well as acquired cellular immune responses.