NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs

Abstract

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 ...

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

“…This phenomenon was observed in both autologous and Killer cell Immunoglobulinlike Receptor mismatched NK-DC cocultures. Ligation of NK-cell receptors could be responsible for this contact dependency [15]; however, the formation of an immunological synapse could also be an important factor [39]. Next to IL-18, other possible candidates are MICA/B [15] and in trans presented IL-15 [15,28].…”

Activated NKT cells imprint NK‐cell differentiation, functionality and education

“…Therefore, the observed changes are most probably the result of synergistic effects mediated by diverse activating cytokines. In this regard, IL-12 was also detected in sera after αGalCerMPEG stimulation and might be relevant for NKT-cell-induced NK-cell differentiation and functionality [42].…”

“…Therefore, the observed changes are most probably the result of synergistic effects mediated by diverse activating cytokines. In this regard, IL-12 was also detected in sera after αGalCerMPEG stimulation and might be relevant for NKT-cell-induced NK-cell differentiation and functionality [42].The transcriptional pathways leading to NK-cell activation are mainly mediated by the transcription factors Eomes and T-bet via . The observed NKT-cellmediated increase in the expression of Eomes might contribute to explain the enhanced secretion of IFNγ.…”

Gene transfer of the CD40‐ligand to human dendritic cells induces NK‐mediated antitumor effects against human carcinoma cells

“…2-4 More recently, Borg et al reported that DC-mediated NK cell activation required the formation of a synapse, which led to IL-12 polarization in DC. 5 In addition to the DC to NK cell contact-dependent mechanism, IL-12 or IFNs secreted from DC are also involved in initiating the activation of NK cells.It has been reported that precursor DC have the ability to produce type1 IFNs,6 and that precursor DC activated by viral infection are induced to increase the production of type1 IFNs, which activate NK cells. 7 CD40L is essential for the activation of DC, followed by the induction of cytokine production.…”

“…[2][3][4] More recently, Borg et al reported that DC-mediated NK cell activation required the formation of a synapse, which led to IL-12 polarization in DC. 5 In addition to the DC to NK cell contact-dependent mechanism, IL-12 or IFNs secreted from DC are also involved in initiating the activation of NK cells.…”