Macrophages Help NK Cells to Attack Tumor Cells by Stimulatory NKG2D Ligand but Protect Themselves from NK Killing by Inhibitory Ligand Qa-1

Abstract

Natural killer (NK) cells and their crosstalk with other immune cells are important for innate immunity against tumor. To explore the role of the interaction between NK cells and macrophages in the regulation of anti-tumor activities of NK cells, we here demonstrate that poly I:C-treated macrophages increased NK cell-mediated cytotoxicity against target tumor cells in NKG2D-dependent manner. In addition, IL-15, IL-18, and IFN-β secreted by poly I:C-treated macrophages are also involved in NKG2D expression and NK cell activation. Interestingly, the increase in expression of NKG2D ligands on macrophages induced a highly NK cell-mediated cytotoxicity against tumor cells, but not against macrophages themselves. Notably, a high expression level of Qa-1, a NKG2A ligand, on macrophages may contribute to such protection of macrophages from NK cell-mediated killing. Furthermore, Qa-1 or NKG2A knockdown and Qa-1 antibody blockade caused the macrophages to be sensitive to NK cytolysis. These results suggested that macrophages may activate NK cells to attack tumor by NKG2D recognition whereas macrophages protect themselves from NK lysis via preferential expression of Qa-1.

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways

“…The binding of these two aNKRs to their putative ligands on target cells enhances NK cell cytotoxicity. The involvement of type I IFN in regulating the expression of NKG2 receptors has been previously reported (55), and our results showing the role of M1-secreted IFN-b in increasing the surface levels of NKG2D extend to a human setting a finding already reported for murine NK cells (45). Interestingly, it has been reported that IL-12 is also able to regulate NKG2D expression on NK cells (46) and that STAT3 is involved in the transcriptional regulation of this aNKR (56).…”

“…3D). These results are also consistent with a recent report describing that IFN-b produced by activated murine macrophages regulates NKG2D expression on NK cells (45). The surface levels of NKG2D on M1-primed NK cells also decreased after the masking of IL-23p19 (Fig.…”

“…The first mechanism relies on the ability of M1-polarized macrophages to synthetize IFN-b (45). We demonstrate that NK cells respond to IFN-b by increasing their surface expression of IL-15Ra and their synthesis of IL-15.…”

Monosodium Urate Crystals Induce Upregulation of NK1.1-Dependent Killing by Macrophages and Support Tumor-Resident NK1.1+ Monocyte/Macrophage Populations in Antitumor Therapy

“…In particular, increased macrophage NKG2D expression has been linked to regulation of granzyme B/perforin-dependent killing functions (26,27), similar to that also reported for NK receptorexpressing DCs (28). Consistent with this, we show that MSU crystal-activated NK1.1 + macrophages also expressed granzyme B and exhibited perforin-dependent cytotoxicity against NKsensitive YAC-1 cells.…”

Critical role of Toll-like receptor signaling in NK cell activation

“…Multiple mechanisms downstream of TLR4 stimulation, such as ATM/ATR kinases and miRNAs, regulate expression of NKG2D ligands, which were involved in the macrophage/ NK cell crosstalk [85]. Our recent published data showed that poly I : C-stimulated murine macrophages can enhance NK cell-mediated anti-tumor effects, which is dependent on the interaction of NKG2D and its ligands RAE-1, H60, and MULT-1 [86]. Similar effects also occur in crosstalk between NK and monocytes.…”