Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell-natural killer cell crosstalk.
Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immune system and have a central role in initiation and regulation of adaptive immune responses. During the early critical immune activities, DCs and NK cells interact and reciprocally regulate each other via cell-cell contact. The molecular mediators of the DC-NK-cell crosstalk are largely undefined. In the present study, we show in mice that DC stimulation of NK-cell IFN-gamma secretion requires DC membrane-bound but not secreted products; is increased by augmenting the expression of DC transmembrane tumor necrosis factor (tmTNF) and NK-cell transmembrane TNF receptor type 2 (tmTNFR2); is inhibited by blocking TNF or TNFR2 but not TNFR1; is impaired by knocking out DC Tnf or NK-cell Tnfr2 but not DC Tnfr1 or Tnfr2 and NK-cell Tnf or Tnfr1; and is restored in TNF-deficient DCs by reconstituting tmTNF, but cannot be mimicked by soluble TNF. We also demonstrate that DC TNF and NK-cell TNFR2 are required for DC-mediated NK-cell proliferation and amplification of cytotoxic activity. These novel findings provide the first evidence that DC-NK-cell crosstalk mediates enhancement of NK-cell functions via triggering NK-cell tmTNFR2 by DC tmTNF.
Xu
Jun
J
University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA, USA.
Chakrabarti
Ayan K
AK
Tan
Jennifer L
JL
Ge
Lisheng
L
Gambotto
Andrea
A
Vujanovic
Nikola L
NL
D000818:Animals; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000276:immunology*
D000998:Antiviral Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma