The Role of Natural Killer Cells in Kidney Transplantation

ABSTRACT: Natural killer (NK) cells are increasingly recognized as central effectors in kidney allograft injury, extending beyond their traditional role in innate immunity. This narrative review summarizes current evidence linking NK cells to microvascular inflammation, with a focus on both antibody-dependent and antibody-independent rejection. In antibody-mediated rejection, NK cells may be activated through Fc gamma receptor IIIa (CD16a) engagement with endothelium-bound donor-specific antibodies, leading to antibody-dependent cellular cytotoxicity and proinflammatory cytokine release. In parallel, emerging data highlight donor-specific antibody-independent pathways of NK cell activation, most prominently "missing-self" recognition, driven by donor-recipient killer immunoglobulin-like receptor-HLA incompatibility. Direct proof of concept for an effector role of NK cells in rejection comes from a series of experimental models. High-dimensional transcriptomic and spatial profiling of clinical transplant biopsies consistently demonstrate NK cell enrichment in antibody-mediated rejection and microvascular inflammation, with expression signatures correlating with graft injury severity and outcomes. Moreover, functional genetic polymorphisms in NK cell receptors, including Fc gamma receptor IIIa and the activating receptor NK group 2 member C, might modulate NK cell responsiveness and as a consequence susceptibility to microvascular injury. Therapeutically, emerging strategies such as CD38-targeting monoclonal antibodies, mammalian target of rapamycin inhibition, and, still in experimental phase, interleukin-15 blockade suggest potential to modulate NK cell activity and counteract rejection. Collectively, these findings position NK cells as central effector cells integrating innate and adaptive alloimmune responses and highlight them as promising therapeutic targets in kidney transplantation.