NKp46 regulates type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity
NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-a (IL-2Ra) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NKp46 reduces IL-2Ra on ILC1s by downregulating NF-?B signaling, thus impairing ILC1 proliferation and cytotoxicity in vitro and in vivo. Likewise, the binding of anti-NKp46 antibody to NKp46 triggers the activation of NF-?B, the expression of IL-2Ra, interferon- ? (IFN-?), tumor necrosis factor (TNF), proliferation, and cytotoxicity. Functionally, NKp46 expressed on mouse ILC1s interacts with tumor cells through cell–cell contact, increasing ILC1 production of IFN-? and TNF, and enhancing cytotoxicity. In a mouse model of acute myeloid leukemia (AML), deletion of NKp46 impairs the ability of ILC1s to control tumor growth and reduces survival. This can be reversed by injecting NKp46+ ILC1s into NKp46 knock-out mice. Human NKp46+ ILC1s exhibit stronger cytokine production and cytotoxicity than their NKp46? counterparts, suggesting that NKp46 plays a similar role in humans. These findings identify an NKp46–NF-?B–IL-2Ra axis and suggest that activating NKp46 with an anti-NKp46 antibody, may provide a potential strategy for anti-tumor innate immunity. Overall design: Comparison of the differences between Ncr1?/? ILC1s and Ncr1gfp/gfp ILC1s