NK-dependent maturation of DCs. NK/DC cross talk has an important role in the process of DC maturation. NK cells are involved in the positive selection of mature myeloid DCs that, after migration to secondary lymphoid compartments, induce priming of Th cells. 73, 74 Primed NK cells upregulate their cytotolytic function and they release cytokines such as TNF-a and IFN-g, which in turn promote the maturation program of DCs that have captured the antigen. [75] [76] [77] At this stage, NK cells acquire the capability to kill autologous iDC, an event that is dependent upon a process of NK cell activation involving the NKp30 receptor 78 and the TNFrelated apoptosis-inducing ligand (TRAIL)-DR4 pathway. 22 NK cells would spare those DCs that after antigen uptake express high levels of HLA class I molecules, whereas they would kill those DCs (recruited in inflamed tissues) that failed to undergo a full maturation. This process involves inhibitory CD94/NKG2A receptors specific for the non-classical HLA-E molecules. 74 mDCs are resistant to NK killing due to the upregulation of HLA class I expression including HLA-E. 79 mDCs also upregulate an array of additional surface molecules including CCR7, CD80, CD86 and HLA class II, which allow their migration to lymph nodes and their optimal interaction with T cells during their priming phase. Thus, during the early phases of inflammation, DC maturation is under the control of NK cells that have a major role in keeping in check the quality of DC undergoing maturation (Figure 2 ). HMGB1 at the crossroad between innate and adaptive immunity. HMGB1 is expressed at the synapse between NK cells and DCs (Figure 3) , and recent studies highlighted the pivotal role of this cytokine during NK-DC cross talk. Semino et al. 80 showed that NK cells trigger immature DCs to polarize and secrete IL-18 at NK-DC synaptic cleft, thus instructing NK cells to release HMGB1, which promotes DC maturation and protects DCs from lysis. Interestingly, the ability of different NK cell subsets to induce DC maturation is unlinked to their phenotypic and cytolytic features but correlates with the relocation of HMGB1 from the nucleus to the cytoplasm, which is strongly enhanced by engagement of the surface molecule NKp30. 81 Moreover, in the presence of DC-derived cytokines, such as IL-12, a cooperation between NKp30 and DNAM-1 to induce NK cells to kill DCs, release TNF-a and promote DC maturation were evidenced. 82 HMGB1 shows a nuclear localization in primary resting NK cells sorted from the blood, and the NK cell activation induces HMGB1 relocalization from the nucleus to the cytosol followed by extracellular release. 21 During the cross talk between activated NK (aNK) cells and iDC, both NK cells and DCs express HMGB1 21 that appears essential for the upregulation of CD80, CD83 and CD86 maturation markers on DCs and for IL-12 production. The HMGB1 secreted during NK-DC cross talk is also essential for Th1 polarization of naïve CD4 T cells, and RAGE is required for HMGB1 effects on DCs. 43, 21 Moreover, the autocrine/paracrine release of HMGB1 is required for the upregulation on DCs of the CCR7 and CXCR4 chemokine receptors and their migration in response to the chemokines receptor ligands CCL19 and CXCL12, respectively, 40 and RAGE has a nonredundant role in DC homing to lymph nodes, as shown in mice by noninvasive imaging by magnetic resonance. 41 Overall, HMGB1-RAGE pathway is activated in DCs that are committed to maturation in peripheral tissues, and it controls the expression of chemokine receptors in DCs that acquire the ability to reach secondary lymphoid organs where they initiate the clonal expansion of Ag-specific T cells. The disruption of HMGB1-RAGE pathway by specific inhibitors 43, 21 or the genetic deletion of RAGE 41 interrupts this circuit, possibly limiting the initiation of T-cell adaptive response. . NK cells and DCs were stained with red and green Cell Trackers, respectively. During the coculture, one NK cell interacted several times with the DC (pointed out with a star), leading to the killing of the DC. The DC died by apoptosis, as shown by the blebs (indicated with the yellow arrows). This editing process occurred very rapidly, within less than 1 min following the kiss of death by NK cells. 22 (e) Mitochondria rearrangement at NK-DC synapse, detected with a green MitoTracker cells. This inhibitory effect of HMGB1 was caused by repression of LTR-mediated transcription. 83 Extracellular HMGB1 also showed a dichotomic effect in different cell types. Addition of HMGB1 to primary monocytes with active HIV-1 infection was reported to suppress viral replication, associated 19 or not associated 20 to HMGB1-mediated increased release of b-chemokines (RANTES, MIP-1a and MIP-1b), strong inhibitors of HIV entry. In contrast, extracellular HMGB1 increased HIV-1 replication in the chronically infected monocytic cell line U1, 19 a process that did not require de novo protein synthesis. 84 HIV-1 induction relied on HMGB1-RAGE interaction, involved p38, ERK and NF-kB pathway, and stimulated the release of TNF-a. 84 Interestingly, HMGB1 could reactivate ex-vivo quiescent HIV-1 from latently infected PBMC collected in aviremic HIV-infected patients. 84 Thus, HMGB1 may reduce viral replication in acute infection by inducing inhibitors of viral entry, but it may trigger viral replication in latently infected cells, including in cells from HIV-infected patients.