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In vivo administration of NKT cell ligand, α-galactosylceramide (α-GalCer), caused the activation of NKT cells to induce a strong NK activity and cytokine production by CD1d-restricted mechanisms. Surprisingly, we also found that α-GalCer induced the activation of immunoregulatory cells involved in acquired immunity. Specifically, in vivo administration of α-GalCer resulted in the induction of the early activation marker CD69 on CD4⁺ T cells, CD8⁺ T cells and B cells in addition to macrophages and NKT cells. However, no significant induction of CD69 was observed on cells from CD1d- or V_α14 NKT-deficient mice, indicating an essential role for the interaction between NKT cells and CD1d-expressing dendritic cells (DC) in the activation of acquired immunity in response to α-GalCer. Indeed, in vivo injection of α-GalCer resulted not only in the activation of NKT cells but also in the generation of CD69⁺CD8⁺ T cells possessing both cytotoxic T lymphocyte (CTL) activity and IFN-γ-producing ability. Tumor-specific CTL generation was also accelerated by α-GalCer. The critical role of CD40-CD40 ligand (CD40L)-mediated NKT-DC interaction during the development of CD69⁺CD8⁺ CTL by α-GalCer was demonstrated by blocking experiments using anti-CD40L mAb. These findings provide direct evidence for a critical role of CD1d-restricted NKT cells and DC in bridging innate and acquired immunity.

Conventional T cells, NK cells and NKT cells have been implicated in the anti-tumor activities induced by IL-12. Here we show that IL-12-induced immune responses are partially impaired in T and NKT cell-deficient RAG-2^-/- mice, and in NKT cell-deficient CD1^-/- mice. In response to a small dose (<1000 U) of IL-12, RAG-2^-/- and CD1^-/- mice demonstrated reduced cytotoxicity, serum IFN-γ elevation and anti-metastatic activities; in contrast, in response to a high dose (>2000U) of IL-12, the IL-12-induced immune responses of RAG-2^-/- and CD1^-/- mice were indistinguishable from wild-type mice. The defective responses to low-dose IL-12 of RAG-2^-/- mice were corrected by adoptive transfer of NKT cells but not NK cells. These findings indicate that both NK and NKT cells contribute to the anti-metastatic responses induced by IL-12, and that NKT cells are mostly responsible for the low-dose activities of this cytokine.

Alloreactivity, the capacity of a large number of T lymphocytes to react with foreign MHC molecules, represents the cellular basis for the rejection of tissue grafts. Although it was originally assumed that the TCR of alloreactive T cells focus their recognition on the polymorphic residues that differ between the MHC molecules of responder and stimulator cells, studies in the MHC class I system have clearly demonstrated that MHC-bound peptides can influence this interaction. It remains unclear, however, whether peptides play an equally important role for the recognition of MHC class II molecules by alloreactive CD4⁺ T cells. Another issue that remains unresolved is the overall frequency of peptide-dependent versus peptide-independent alloreactive T cells. We have addressed these questions with antigen-presenting cells (APC) from H2-M mutant mice that predominantly express a single MHC class II-peptide complex, H2-A^b bound by a peptide (CLIP) derived from the class II-associated invariant chain. APC from these mice were used as targets and stimulators for alloreactive CD4⁺ T cells. Results demonstrated that the vast majority of CD4⁺ alloreactive T cells recognize MHC class II molecules in a peptide-dependent fashion.