Immune cells that are activated in response to bacterial and viral antigens presented by the MHCI-like molecule CD1d have been classified as type I and type II NKT cells. Type I NKT cells express a semi-invariant TCR-αβ encoded by the Vα14 (Vα24 in humans) and Jα18 gene segments, and therefore are also known as invariant NKT (iNKT) cells. In contrast, type II NKT (non-iNKT) cells express variable non-Vα14Jα18 TCR, are distinct from the Vα14+ iNKT cells, and potentially recognize a wider profile of glycolipid ligands.[75, 76] In mice and humans, iNKT cells have been identified using CD1d tetramers loaded with α-galactosyl ceramide (GalCer). Non-iNKT cells are less well characterized and have only been indirectly studied by comparing immune responses in mice either deficient in both subsets (CD1d−/−) or only iNKT cells (Jα18−/−). Stimulation of iNKT cells has been shown to be beneficial for the downstream activation of T and NK cells in experimental tumour models,[7, 77] whereas the activation of non-iNKT cells seems to be deleterious.[7, 78] This differential effect on tumours may be explained by cytokine profiles generated following the activation of each cell type. For example, presentation of α-GalCer by a DC to the TCR of iNKT cells led to the generation of IL-12, IFN-γ, tumour necrosis factor and the subsequent activation of anti-tumorigenic CTL. In contrast, the activation of non-iNKT cells through endogenous ligands, such as lysophosphatidylcholines, leads to the production of IL-4, IL-13 and TGF-β, which subsequently impairs CTL and NK cell functions.[79, 81] Interleukin-13 has been reported to mediate its effect via the IL-4R–STAT6 pathway and can induce TGF-β-producing CD11b+ Gr-1+ MDSC.[82, 83] Instead, Ko et al. showed that iNKT cells activated by α-GalCer-loaded CD11b+ Gr-1+ MDSC could convert these MDSC into stimulatory APC. Such reprogrammed MDSC up-regulated the expression of CD11b, CD11c and CD86, did not suppress Teff cells and thereby supported the generation of antigen-specific CTL immunity without increasing Treg-cell levels. The mechanism is not completely understood, but may involve soluble mediators and cell-to-cell contact interactions. Indeed, production of IFN-γ by α-GalCer-activated iNKT cells required direct CD40/CD40L interactions with DC. This interaction enhanced IL-12 secretion by DC and further functions to transactivate iNKT cells. In a mouse model of breast cancer, anti-tumour efficacy of CTL was partly dependent on the presence of ex vivo expanded iNKT cells that rendered these CTL more resistant to the immunosuppressive actions of MDSC. Furthermore, it has been proposed that activated iNKT cells can limit the growth of human neuroblastomas in NOD/SCID xenografts by selectively killing IL-6-producing CD1d+ CD68+ TAM. Additionally, it might be rewarding to investigate the interaction between iNKT cells and TAN, because iNKT cells from melanoma patients have been reported to modulate the suppressive capacity of serum amyloid A (SAA) -1 differentiated IL-10-secreting neutrophils by increasing the IL-12 production of these cells. SAA-1 promotes the interaction between iNKT cells and neutrophils in a CD1d-dependent and CD40-dependent manner, suggesting that iNKT cells can modulate the expansion and differentiation of neutrophils, possibly by interacting with CD1d+ immature myeloid cells in the bone marrow. In contrast, mature neutrophils can modulate IFN-γ, tumor necrosis factor and IL-4 production by iNKT cells in mice and humans. Therefore, depending on the context, iNKT cells are able to potentiate pro-inflammatory neutrophil functions whereas neutrophils can down-regulate iNKT cell responses. To examine the interaction between iNKT cells and DC during the generation of anti-tumour immunity, Gillessen et al. vaccinated wild-type (WT), CD1d−/− and Jα18−/− mice with irradiated GM-CSF-secreting B16F10 melanoma cells. This vaccination strategy enhanced tumour antigen presentation by recruited CD8α− CD11c+ DC in WT mice. These DC expressed high levels of CD1d and macrophage inflammatory protein-2, a chemokine involved in iNKT-cell recruitment. Indeed, GM-CSF augmented the numbers of CD1d-restricted iNKT cells in vivo. In contrast, the vaccinated CD1d−/− and Jα18−/− mice lacked iNKT cell-mediated anti-tumour immunity and DC from CD1d−/− mice showed compromised maturation and function. These results provide further evidence for a role of iNKT–myeloid cell cross-talk shaping anti-tumour immunity. Furthermore, influenza A virus infected CD1d−/− mice provoke an expansion of immunosuppressive CD11b+ Ly-6G+ Ly-6C+ cells, which inhibits antigen-specific immune responses. In this model, adoptive transfer of iNKT cells abolished the suppressive activity of MDSC through CD1d-dependent and CD40-dependent interactions. As patients with cancer often have lower frequencies of iNKT cells than healthy donors,[93, 94] adoptive transfer of activated iNKT cells could become part of a treatment modality for cancer. Collectively, these findings show that NKT cells are potent immunomodulators of myeloid cells. Given their potential to influence anti-tumour effector activities, iNKT cells may represent an underestimated immune population to be used in cancer immunotherapy.