TNFR2 and IL-12 coactivation enables slanDCs to support NK-cell function via membrane-bound TNF-α

Human blood NK cells exert strong cytotoxicity against transformed cells and produce different cytokines and chemokines with an important role in modulating immune responses. However, the nature of NK-cell function depends on NK-cell interaction with other immune cells. One type of immune cells that communicate with NK cells are 6-sulfo LacNAc DCs (slanDCs), which comprise a major subpopulation of proinflammatory human blood DCs. In this study, we investigated the molecular mechanisms by which slanDCs interact with NK cells. Our in vitro studies demonstrate that LPS-stimulated slanDCs enhance activation and function of NK cells essentially via membrane-bound TNF-α (mTNF-α). LPS stimulation upregulates expression of mTNF-α in slanDCs, and surface TNF receptor 2 (TNFR2) is upregulated on NK cells after coincubation with slanDCs. IL-12 secreted by slanDCs increases surface expression of TNFR2 in NK cells. TNFR2 signaling in NK cells leads to activation of NF-κB, a transcription factor for cytokines such as GM-CSF. GM-CSF provided by NK cells is responsible for enhancing IL-12 secretion in slanDCs. In conclusion, TNFR2 and IL-12 signaling, which support one another, enables slanDCs to enhance NK-cell function through mTNF-α, thereby regulating immune responses.