[IL]-4, IL-10, IL-13). 4,9-11 NKT cells have also been reported to exhibit direct cytotoxicity against tumor target cells, 8,[12][13][14] which has made it difficult to predict the consequences of their activation in vivo but nonetheless has caused much speculation that they play a central role in immunoregulation. Accumulated experimental evidence has supported their role in promoting innate antitumor immunity 8,14-17 while paradoxically suppressing acquired antitumor immunity 18 and autoimmunity 19 and maintaining some forms of tolerance. [20][21][22] These results have ensured continued debate and confirmed the central role these cells play in the immune system. 23,24 The ␣-galactosylceramide (␣-GalCer) is chemically and functionally analogous to natural glycolipids first purified from marine sponges on the basis of their antitumor properties against B16 melanoma. 25,26 ␣-GalCer is presented by CD1d, leading to specific stimulation of NKT cells. 4,10,11,27 The antitumor effect of ␣-GalCer is observed against various tumor cells of different origins, including melanomas, lung, colon, and renal cell carcinomas, erythroleukemias, and other hematopoietic malignancies. 25,26,[28][29][30] In vivo, the antitumor activities of ␣-GalCer and IL-12 are similar, whereas in vitro it has been demonstrated that the production of IFN-␥ by NKT cells in response to ␣-GalCer requires IL-12 produced by dendritic cells (DCs) 31 and direct contact between NKT cells and DCs through CD40-CD40 ligand interactions. Both ␣-GalCer and low doses of IL-12 are strong inducers of NKT cell activity and will not exert their antitumor activities in the absence of NKT cells. 8,[15][16][17] Despite these findings, little is known about the precise sequence of events and factors involved in ␣-GalCerinduced tumor suppression.We know that recognition of the ␣-GalCer-CD1d complex leads to NKT cell activation. 10,11,27 This results in rapid production (within hours) of Th1 and Th2 cytokines by NKT cells, 32 rapid elimination of NKT cells after they produce cytokines, [33][34][35][36] proliferation and activation of NK cells 4,10,32,37 and subsequent IFN-␥ production, 38 and bystander activation of immune responses mediated by conventional T cells and B cells. 32,33,[39][40][41][42][43] NK cell activation was at least partly dependent on IFN-␥. 32,33,39 Although ␣-GalCer For personal use only. on May 9, 2018. by guest www.bloodjournal.org From has been shown to induce perforin-dependent cytotoxicity by NKT and NK cells, the significance of this pathway in vivo is less clear. Our previous study 30 and more recently that of Hayakawa et al 38 have demonstrated that the antimetastatic effect of ␣-GalCer was impaired in NK cell-depleted or IFN-␥-deficient mice. Collectively, these results indicate an important role for NKT and NK cells and the cytokine IFN-␥ after ␣-GalCer administration. Despite these clues, none of the previous studies have defined the sequence of events after ␣-GalCer treatment, nor was it known whether IFN-␥ production by NKT cells, NK...
Natural killer (NK) cells may modulate the development of adaptive immune responses, but until now there has been little evidence to support this hypothesis. We investigated the primary and secondary immunity elicited by various tumor cell lines that express CD70 and interact with CD70 ligand (CD27), which is constitutively expressed on NK cells. CD70 expression enhanced primary tumor rejection in vivo as well as T cell immunity against secondary tumor challenge. Primary rejection of major histocompatibility complex (MHC) class I-deficient RMA-S.CD70 tumor cells was mediated by NK cells and perforin- and interferon-gamma-dependent mechanisms. This NK cell-mediated process also efficiently evoked the subsequent development of tumor-specific cytotoxic and T helper type 1 responses to the parental, MHC class I-sufficient, RMA tumor cells. Thus CD27-CD70 interactions provide a key link between innate NK cell responses and adaptive T cell immunity.
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