Signal Transduction in Natural Killer Cells

Macfarlane, Alexander W.; Campbell, Kerry S.

doi:10.1007/3-540-27743-9_2

Cited by 73 publications

(82 citation statements)

References 198 publications

(221 reference statements)

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“…Increased IL-12 production by TLA-pulsed DC is mediated by NKG2D, an activating receptor on human and murine NK cells (37), because Ab to this molecule significantly reduces the level of cytokine production. Moreover, upon priming with TLA, increased expression of NKG2D ligands, RAE-1 and MULT-1, on the DC was observed.…”

Section: Discussionmentioning

confidence: 99%

NK Cells Enhance Dendritic Cell Response against Parasite Antigens via NKG2D Pathway

Guan

Moretto

Bzik

et al. 2007

The Journal of Immunology

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Recent studies have shown that NK-dendritic cell (DC) interaction plays an important role in the induction of immune response against tumors and certain viruses. Although the effect of this interaction is bidirectional, the mechanism or molecules involved in this cross-talk have not been identified. In this study, we report that coculture with NK cells causes several fold increase in IL-12 production by Toxoplasma gondii lysate Ag-pulsed DC. This interaction also leads to stronger priming of Ag-specific CD8+ T cell response by these cells. In vitro blockade of NKG2D, a molecule present on human and murine NK cells, neutralizes the NK cell-induced up-regulation of DC response. Moreover, treatment of infected animals with Ab to NKG2D receptor compromises the development of Ag-specific CD8+ T cell immunity and reduces their ability to clear parasites. These studies emphasize the critical role played by NKG2D in the NK-DC interaction, which apparently is important for the generation of robust CD8+ T cell immunity against intracellular pathogens. To the best of our knowledge, this is the first work that describes in vivo importance of NKG2D during natural infection.

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Section: Discussionmentioning

confidence: 99%

NK Cells Enhance Dendritic Cell Response against Parasite Antigens via NKG2D Pathway

Guan

Moretto

Bzik

et al. 2007

The Journal of Immunology

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“…25). A large number of activating and costimulatory molecules potentially contribute signals leading to the polarization of the NK cell and lytic granules required for effective killing of the target.…”

mentioning

confidence: 99%

Perforin-Dependent Cryptococcal Microbicidal Activity in NK Cells Requires PI3K-Dependent ERK1/2 Signaling

Wiseman¹,

Ling²,

Marr³

et al. 2007

The Journal of Immunology

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Previously, NK cells have been reported to kill the opportunistic fungal pathogen Cryptococcus neoformans through a perforin-dependent mechanism; however, the receptor and signaling involved are unknown. In this report we sought to identify the signaling pathways activated and required for direct perforin-mediated killing of microbes. In this study, using the NK-like cell line YT and primary peripheral blood NK cells, it is demonstrated that YT cells kill C. neoformans and that the killing is accompanied by the activation of PI3K. We demonstrate that inhibition of either the catalytic subunit (using a pharmacological inhibitor) or the α-regulatory subunit (using small interfering RNA knockdown) of PI3K significantly inhibited the killing of C. neoformans. Downstream of PI3K, ERK1/2 was activated in a PI3K-dependent fashion and was required for cryptococcal killing. Furthermore, we demonstrate that perforin release from YT cells can be detected by 4 h after contact of the YT cells with C. neoformans and that the release of perforin is blocked by pharmacological inhibition of either PI3K or ERK1/2. Defective degranulation is rooted in the inability to polarize perforin-containing granules toward the target. Finally, we demonstrate that PI3K-ERK1/2-dependent signaling is activated and required for the killing of C. neoformans by primary NK cells. Taken together, these data identify a conserved PI3K-ERK1/2 pathway that is used by NK cells during the direct killing of C. neoformans and demonstrate that the pathway is essential in the formation and activation of the microbicidal mechanism.

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“…SHP-1/2 activation leads to the suppression of activating receptor signals (Long, 2008). Activating KIR possess a positively charged residue (usually arginine) in the transmembrane region, which facilitate the association with accessory molecules, DAP12 or FcεRIγ (KIR2DL4) and NK cell activation (cytotoxicity and/or cytokine production) (MacFarlane and Campbell, 2006). The exception, KIR2DL4 contains both ITIMs and a positively charged residue (lysine), which facilitates the association with FcεRIγ and the induction of the activating signals (Kikuchi-Maki et al, 2005).…”

Section: Kir Structure and Signalling Functionmentioning

confidence: 99%