Mature dendritic cells (mDCs) can trigger the effector functions of natural killer (NK) cells. Knockout , small-interfering RNA or neutralizing antibodies targeting interleukin 12 (IL-12) subunits revealed a critical role for IL-12 in NK cell interferon (IFN-) secretion promoted by mDCs. However, NK cell activation by DCs also required direct cell-to-cell contacts. DC-mediated NK cell activation involved the formation of stimulatory synapses between DCs and NK cells. The formation of DC/NK cell conjugates depended on cy-toskeleton remodeling and lipid raft mobilization in DCs. Moreover, the disruption of the DC cytoskeleton using pharmaco-logic agents or the loss-of-function mutation of the Wiskott-Aldrich syndrome protein abolished the DC-mediated NK cell activation. Synapse formation promoted the polarized secretion of preassembled stores of IL-12 by DCs toward the NK cell. The synaptic delivery of IL-12 by DCs was required for IFN-secretion by NK cells, as assessed using inhibitors of cytoskel-eton rearrangements and transwell experiments. Therefore, the cross-talk between DCs and NK cells is dictated by functional synapses. (Blood. 2004;104:3267-3275) Introduction Natural killer (NK) cells recognize and kill target cells expressing virus-encoded proteins, as well as tumor cells that have lost the expression of major histocompatibility complex (MHC) class I antigens. 1-5 Activation of NK cells results from a balance between inhibitory and activating signaling pathways. 6 Incompatibilities in HLA-Cw alleles between NK and target cells promote the cytolytic function of NK cells involved in the graft-versus-leukemia reaction. 7 In contrast, receptor-ligand interactions between MHC class I molecules and killer inhibitory immunoglobulin-like receptor (KIR) or lectin-type inhibitory NK cell receptor can initiate a dominant inhibitory signaling cascade that blocks NK cell cytotoxicity. Recent studies of the physical interaction between NK cells and target cells have highlighted the functional impact of its synaptic organization. Thus, Lou et al 8 reported that, within the NK/ target cell synapse, lipid rafts polarized to the site of the cell contact in conjugates with sensitive MHC class I-negative targets but not in conjugates with resistant MHC class I-positive targets. Moreover, the negative signals between an NK cell and a target cell are transmitted by KIR at the site of membrane apposition, where inhibitory receptors become clustered with MHC class I ligands in a supramolecular structure known as an inhibitory NK immune synapse (IS). 9,10 KIR signaling is critical for blocking lipid raft polarization and NK cell cytotoxicity, both depending on movements of microtubuli and actin filaments. 11 The composition of adhesion, costimulatory, cytoskel-etal, and signaling molecules in the supramolecular activation clusters (SMACs) of the cytolytic and noncytolytic NK cell IS revealed profound differences. 12 Indeed, cytoskeleton remodel-ing and redistribution of NK cell signaling molecules occur mainly in cytolytic NK ...

HTLV‐I transformed T cells not only express a large number of interleukin‐2 receptors [IL‐2R/p55(Tac)], but also produce a factor named ATL‐derived factor (ADF) that augments the expression of IL‐2R/p55(Tac). Based on a partial N‐terminal amino acid sequence, complementary DNA (cDNA) clones for human and mouse ADF were isolated and sequenced. Recombinant ADF produced by COS‐7 monkey kidney cells showed IL‐2R/Tac inducing activity on YT cells, which are sensitive for ADF. ADF mRNA was strongly expressed in HTLV‐I(+) T cells lines, but not in inactivated cells (THP‐1, unstimulated PBMC). Furthermore, in normal human peripheral blood mononuclear cells, the expression of ADF mRNA was enhanced by mitogens or phorbol myristate acetate, suggesting a possible involvement of ADF in the lymphocyte activation. Homology analysis revealed an unexpected relationship between ADF and dithiol‐reducing enzyme, thioredoxin, involved in many important biological reactions such as the conversion of ribonucleotides into deoxyribonucleotides, or the stabilization of glucocorticoid receptors. The biological significance of the generation of a redox potential in lymphocyte activation, and the possible involvement of dithiol reduction in the induction of IL‐2R/Tac are discussed.