Submitted June 1, 2006
Accepted December 5, 2006
Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell-natural killer cell cross-talk
Jun Xu, Ayan K Chakrabarti, Jennifer L Tan, Lisheng Ge, Andrea Gambotto, and Nikola L Vujanovic*
First Affiliate Hospital, Guangzhou Medical College, Guangzhou, Guangdong, China
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Dept of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Depts of Surgery, and Molecular Genetics & Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
* Corresponding author; email: vujanovicnl{at}msx.upmc.edu.
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 cross-talk are largely undefined. In the present study, we show in mice that DC stimulation of NK-cell IFN-
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-2 (tmTNFR2); inhibited by blocking TNF or TNFR2, but not TNFR1; impaired by knocking out DC TNF or NK-cell TNFR2, but not DC TNFR1 or TNFR2 and NK-cell TNF or TNFR1; restored in TNF-deficient DCs by reconstituting tmTNF, but can't 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 cross-talk mediates enhancement of NK-cell functions via triggering NK-cell tmTNFR2 by DC tmTNF.
