Interleukin-1 receptor 8 (IL-1R8) plays a crucial role in natural killer (NK) cell differentiation and function

IL-1R8 is an Interleukin-1R like receptor (ILR) family member that acts as a negative regulator of ILRs and TLRs signaling. Both murine and human NK cells express high levels of IL-1R8 but its functional role in this cell type has not been described so far. The results presented here show that IL-1R8 expression increases along NK cell maturation in the mouse. IL-1R8 expression and regulation in NK cells are conserved in humans, both in terms of mRNA and protein expression. Taking advantage of IL-1R8-deficient mice, we found that IL-1R8 deficiency is associated with higher frequency and absolute number of mature NK cells in blood, spleen, bone-marrow and liver. IL-1R8 deficient NK cells display increased Interferon-\uf067 (IFN-\uf067) production and higher cytotoxic activity. IL-1R8 deficiency is also associated with higher expression of NK cell activating receptors (NKG2-D and DNAM-1), a more differentiated phenotype of NK cells (Ly49s and CD94) and increased activation of the mTOR pathway. Finally, to address the relevance of IL-1R8 in NK cells in vivo, we used a model of transplantable MCA-fibrosarcoma, whose metastatization in the lung is controlled by NK cells. The primary tumor similarly grew in IL-1R8-competent and deficient mice, whereas the number and dimension of lung metastasis were significantly reduced in IL-1R8-deficient mice. The depletion of NK cells in this model totally abrogated the protection from lung metastasis in IL-1R8-deficient mice. IL-1R8 plays therefore a non-redundant role in the regulation of NK cell biology and could be a crucial regulator of NK cell antitumoral activity