The yin-yang of the interaction between myelomonocytic cells and NK cells

Abstract

NK cells are innate lymphoid cells, which play a key role in the immune response to cancer and pathogens and participate in the shaping of adaptive immunity. NK cells engage in a complex bidirectional interaction with myelomonocytic cells. In particular, macrophages, dendritic cells and neutrophils promote differentiation and effector function of NK cells and, on the other hand, myelomonocytic cells express triggers of checkpoint blockade (eg PD-L1) and other immunosuppressive molecules, which negatively regulate NK cell function. In addition, NK cells express high levels of IL-1R8, which acts as a checkpoint for IL-18 driven differentiation and activation of NK cells. Evidence suggests that targeting the myeloid cell-NK cell crosstalk unleashes effective anti-tumour and anti-viral resistance.

Figure 1. NK cell activation mediated by dendritic cells, neutrophils and macrophages.

Both soluble factors and cell-to-cell contact are involved in the induction or boosting of NK cell effector functions. DCs, neutrophils and macrophages produce IL-12, IL-18, IFNβ, TNFα and IL-15 which induce NK cell activation. IFNβ is responsible for the production of IL-15, which can occur not only in DCs but also in NK cells themselves.

Figure 2. IL-18 as a central player in NK cell activation.

IL-18 is a crucial proinflammatory cytokine promoting NK cell activation. M0 and M2 macrophages express a membrane-bound form of IL-18 (mIL-18), which is released upon treatment with LPS. IL-18 release by macrophages favors NK cell activation. DCs express IL-18 upon microbial product exposure and a cell-to-cell proximity is required in order to trigger a full NK cell activation.

Figure 3. Suppression of NK cell function by macrophages.

NK cell suppression mediated by TAM-derived PGE₂, TGFβ and the engagement of PD-1 by macrophage-expressed PD-L1. MΦ: macrophage; TAM: tumor associated macrophage.