Dataset Information

Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell-natural killer cell crosstalk.

ABSTRACT: 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.

SUBMITTER: Xu J

PROVIDER: S-EPMC1852244 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell-natural killer cell crosstalk.

Xu Jun J Chakrabarti Ayan K AK Tan Jennifer L JL Ge Lisheng L Gambotto Andrea A Vujanovic Nikola L NL

Blood 20061212 8

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 membr ...[more]

PMID: 17164346

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Project description:The importance of the bi-directional natural killer-dendritic cell crosstalk in coordinating anti-tumour and anti-microbial responses in vivo has been well established. However, physical parameters associated with natural killer-dendritic cell interactions have not been fully elucidated. We have previously used a simple "Y" shaped microfluidic device to study natural killer cell-migratory responses toward chemical gradients from a conditioned medium of dendritic cells. There are, however, limitations of the Y-shaped microfluidic devices that could not support higher throughput analyses and studies of cell-cell interactions. Here, we report two novel microfluidic devices (D3-Chip, T2-Chip) we applied in advanced studies of natural killer-cell migrations and their interactions with dendritic cells in vitro. The D3-Chip is an improved version of the previously published Y-shaped device that supports high-throughput analyses and docking of the cells of interest in the migration assay before they are exposed to a chemical gradient. The T2-Chip is created to support analyses of natural killer-dendritic cell cell-cell interactions without the requirement of promoting a natural killer cell to migrate long distances to find a loaded dendritic cell in the device. Using these two microfluidic platforms, we observe quantitative differences in the abilities of the immature and lipopolysaccharide-activated mature dendritic cells to interact with activated natural killer cells. The contact time between the activated natural killer cells and immature dendritic cells is significantly longer than that of the mature dendritic cells. There is a significantly higher frequency of an immature dendritic cell coming into contact with multiple natural killer cells and/or making multiple simultaneous contacts with multiple natural killer cells. To contrast, an activated natural killer cell has a significantly higher frequency of coming into contact with the mature dendritic cells than immature dendritic cells. Collectively, these differences in natural killer-dendritic cell interactions may underlie the differential maturation of immature dendritic cells by activated natural killer cells. Further applications of these microfluidic devices in studying natural killer-dendritic cell crosstalk under defined microenvironments shall enrich our understanding of the functional regulations of natural killer cells and dendritic cells in the natural killer-dendritic cell crosstalk.

Project description:BackgroundBone marrow derived endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) involved in neo-angiogenesis and endothelial homeostasis and are considered as a circulating reservoir for endothelial repair. Many studies showed that EPCs from patients with cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition increases the chance of immune rejection, especially by T cells, before exerting the desired regenerative functions. TNF? is one of the main mediators of EPC activation that recognizes two distinct receptors, TNFR1 and TNFR2. We have recently reported that human EPCs are immunosuppressive and this effect was TNF?-TNFR2 dependent. Here, we aimed to investigate if an adequate TNF? pre-conditioning could increase TNFR2 expression and prime EPCs towards more immunoregulatory functions.MethodsEPCs were pre-treated with several doses of TNF? to find the proper dose to up-regulate TNFR2 while keeping the TNFR1 expression stable. Then, co-cultures of human EPCs and human T cells were performed to assess whether TNF? priming would increase EPC immunosuppressive and immunomodulatory effect.ResultsTreating EPCs with 1 ng/ml TNF? significantly up-regulated TNFR2 expression without unrestrained increase of TNFR1 and other endothelial injury markers. Moreover, TNF? priming through its interaction with TNFR2 remarkably enhanced EPC immunosuppressive and anti-inflammatory effects. Conversely, blocking TNFR2 using anti-TNFR2 mAb followed by 1 ng/ml of TNF? treatment led to the TNF?-TNFR1 interaction and polarized EPCs towards pro-inflammatory and immunogenic functions.ConclusionsWe report for the first time the crucial impact of inflammation notably the TNF?-TNFR signaling pathway on EPC immunological function. Our work unveils the pro-inflammatory role of the TNF?-TNFR1 axis and, inversely the anti-inflammatory implication of the TNF?-TNFR2 axis in EPC immunoregulatory functions. Priming EPCs with 1 ng/ml of TNF? prior to their administration could boost them toward a more immunosuppressive phenotype. This could potentially lead to EPCs' longer presence in vivo after their allogenic administration resulting in their better contribution to angiogenesis and vascular regeneration. Video Abstract.

Dataset Information

Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell-natural killer cell crosstalk.

Publications

Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell-natural killer cell crosstalk.

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