title: TNFR2 and IL-12 coactivation enables slanDCs to support NK-cell function via membrane-bound TNF-α.
abstract: 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-kB, 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.
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors.forename: Dejene M
authors.initials: DM
authors.lastname: Tufa
authors.forename: Debanjana
authors.initials: D
authors.lastname: Chatterjee
authors.forename: Hui Z
authors.initials: HZ
authors.lastname: Low
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Roland
authors.initials: R
authors.lastname: Jacobs
mesh_terms: D000606:Amino Sugars / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: C467438:6-sulfo-LacNac; D000606:Amino Sugars; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: NK-cell stimulation; TNFR2 upregulation; cell-cell contact; mTNF-α; slanDCs