Abstract
Natural Killer (NK) cells confer protection from tumors and infections by releasing cytotoxic granules and pro-inflammatory cytokines upon recognition of diseased cells. The responsiveness of NK cells to acute stimulation is dynamically tuned by steady-state receptor-ligand interactions of an NK cell with its cellular environment. Here, we demonstrate that in healthy WT mice the NK activating receptor NKG2D is engaged in vivo by one of its ligands, RAE-1ε, which is expressed constitutively by lymph node endothelial cells and highly induced on tumor-associated endothelium. This interaction causes internalization of NKG2D from the NK cell surface and transmits an NK-intrinsic signal that desensitizes NK cell responses globally to acute stimulation, resulting in impaired NK antitumor responses in vivo.
Highlights
Natural Killer (NK) cells are key effectors in the immune response to pathogens and tumors (Vivier et al, 2008)
Cell surface NKG2D ligand expression is usually considered a hallmark of unhealthy cells, but expression on the surface of normal cells in healthy animals has not been exhaustively surveyed in vivo
Blocking RAE-1e in WT mice increased NKG2D to levels comparable to RAE-1KO mice at steady state, whereas anti-RAE-1e had no effect on NKG2D levels in RAE-1-KO mice (Figure 1—figure supplement 1C)
Summary
Natural Killer (NK) cells are key effectors in the immune response to pathogens and tumors (Vivier et al, 2008). NK cells recognize unhealthy cells using an array of cell surface receptors (Vivier et al, 2011; Marcus et al, 2014; Moretta et al, 2014; Morvan and Lanier, 2016) These receptors transmit activating or inhibitory signals upon binding cognate ligands on the target cell, and the net balance of these signals dictates whether the NK cell response is triggered. Mice lacking MHC I molecules or inhibitory Ly49 receptors show dramatically weaker NK responses to a wide variety of acute stimulatory signals in vitro and in vivo (Liao et al, 1991; Fernandez et al, 2005; Kim et al, 2005; Anfossi et al, 2006; Brodin et al, 2009; Joncker et al, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
