Abstract
NF-κB is a key transcription factor that dictates the outcome of diverse immune responses. How NF-κB is regulated by multiple activating receptors that are engaged during natural killer (NK)-target cell contact remains undefined. Here we show that sole engagement of NKG2D, 2B4 or DNAM-1 is insufficient for NF-κB activation. Rather, cooperation between these receptors is required at the level of Vav1 for synergistic NF-κB activation. Vav1-dependent synergistic signalling requires a separate PI3K-Akt signal, primarily mediated by NKG2D or DNAM-1, for optimal p65 phosphorylation and NF-κB activation. Vav1 controls downstream p65 phosphorylation and NF-κB activation. Synergistic signalling is defective in X-linked lymphoproliferative disease (XLP1) NK cells entailing 2B4 dysfunction and required for p65 phosphorylation by PI3K-Akt signal, suggesting stepwise signalling checkpoint for NF-κB activation. Thus, our study provides a framework explaining how signals from different activating receptors are coordinated to determine specificity and magnitude of NF-κB activation and NK cell responses.
Highlights
nuclear factor-kB (NF-kB) is a key transcription factor that dictates the outcome of diverse immune responses
The signalling pathways leading to NF-kB activation in natural killer (NK) cells have been characterized to some extent, but such studies are mostly confined to a few NK cell-activating receptors associated with immunoreceptor tyrosine-based activation motif (ITAM)-bearing adaptor molecules such as DAP12, FcRg and CD3z
Such an increase was distinct from Akt phosphorylation, which is downstream of PI3K activation via NKG2D but not 2B4 (Fig. 1a)
Summary
NF-kB is a key transcription factor that dictates the outcome of diverse immune responses. The signalling pathways leading to NF-kB activation in NK cells have been characterized to some extent, but such studies are mostly confined to a few NK cell-activating receptors associated with immunoreceptor tyrosine-based activation motif (ITAM)-bearing adaptor molecules such as DAP12, FcRg and CD3z (refs 20,21). These include NKp30 in humans and NK1.1, Ly49D, Ly49H, CD16 and NKG2D in mice. The signalling pathways downstream of ITAM-coupled receptors in NK cells are considered similar to those triggered by the antigen-specific receptors on B and T cells[9] It remains unclear how the signalling cascades induced by non-ITAM-associated receptors (for example, NKG2D, 2B4, DNAM-1) are coupled to NF-kB activation. Because of multiple receptor–ligand interactions that occur during NK-target cell contact, it is important to understand how signals from different NK cell receptors are coordinated to control NF-kB activation
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