Impact of bone marrow-derived signals on NK cell development and functional maturation

Natural killer (NK) cells are cytotoxic members of type I innate lymphocytes (ILC1) with a prominent role in anti-tumor and anti-viral immune responses. Despite the increasing insight into NK cell biology, the steps and stages leading to mature circulating NK cells require further investigation. Natural killer cell development and functional maturation are complex and multi-stage processes that occur predominantly in the bone marrow (BM) and originate from haematopoietic stem cells CD34⁺ (HSC). Within the BM, NK cell precursor (NKP) and NK cell development intermediates reside in specialized niches that are characterized by particular cellular components that provide signals required for their maturation. These signals consist of soluble factors or direct cellular-contact interactions mediated by cytokines and growth factors with complementary, as well as overlapping roles in distinct developmental steps. Emerging evidence highlights the plasticity of the early phase of NK cell development, and the capacity of different signal combinations to redirect precursor lineage commitment through other innate cell populations. Here, we summarize the role of signals known to guide NK cell differentiation with a particular focus on the cytokines and the receptor/ligand pairs playing a critical role in these processes. A comprehensive understanding of the mechanisms underlying NK cell development will elucidate their roles in pathological conditions and will improve protocols for NK cell therapeutic application.