Natural killer cells in kidney immune surveillance, injury and fibrosis

Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system with essential roles in immune surveillance, tissue homeostasis and inflammation. In the kidney, NK cells comprise a heterogeneous population that includes both circulating and tissue-resident subsets, each shaped by environmental cues and genetic factors through interactions with major histocompatibility complex class I molecules. The latest research data highlight multifaceted NK cell contributions to kidney physiology and pathology. In steady state, NK cells support kidney immune surveillance and crosstalk with epithelial, myeloid and lymphoid cells. In disease, NK cells can promote injury through direct cytotoxicity and pro-inflammatory cytokine release. Experimental models demonstrate pathogenic roles for NK cells in ischaemia-reperfusion injury and chronic kidney disease, with emerging evidence implicating NK cell-derived mediators in fibrogenesis. In kidney transplantation, NK cells are effectors of antibody-dependent and antibody-independent allograft injury. Educated NK cells expressing CD16a (also known as FcγRIIIa) mediate antibody-dependent cellular cytotoxicity, whereas loss of inhibitory receptor-ligand interactions (for example, due to killer immunoglobulin-like receptor-HLA mismatch) can trigger NK cell activation independently of donor-specific antibodies. Advances in high-resolution profiling have deepened mechanistic insights and uncovered novel therapeutic targets. Here, we provide a comprehensive overview of NK cell biology in the kidney, highlighting roles in health, disease and transplantation, and we consider its translational implications for diagnosis and therapy.