Natural Killer Cells in Kidney Transplantation: Dual Role in Allograft Injury and Immune Adaptation

Abstract

Kidney transplantation is the optimal treatment for end-stage renal disease, yet long-term graft survival remains limited by allograft rejection. While T and B cells and donor-specific antibodies (DSA) have been the main focus, accumulating evidence indicates that natural killer (NK) cells play a significant dual role in both graft injury and immune adaptation, including in DSA-negative rejection. This narrative review summarizes current knowledge on the dual role of NK cells in kidney transplantation, with emphasis on antibody-independent mechanisms, adaptive NK-cell subsets, and their potential as biomarkers of graft outcome. NK cells are highly heterogeneous, consisting of CD56 ^bright and CD56 ^dim CD16 subsets. Cytomegalovirus infection promotes expansion of adaptive NKG2C ⁺ CD57 ⁺ cells with memory-like features. In rejection, NK cells act through both antibody-dependent cellular cytotoxicity and antibody-inde-pendent pathways, such as “missing-self” recognition via killer immunoglobulin-like receptors (KIR)/human leukocyte antigen (HLA) mismatch and release of the killer-specific secretory protein of 37 kDa (Ksp37). Specific NK subsets are associated with microvascular inflammation and graft loss even in the absence of DSA. In contrast, NK cells support tolerance by killing donor dendritic cells and activated T cells, producing interleukin (IL)-10 and transforming growth factor-β (TGF-β), and undergoing reeducation, gradually shifting from a cytotoxic to a regulatory phenotype. NK cells exert a dual, often opposing role in kidney transplantation, mediating both allograft injury and immune tolerance. Better understanding of their plasticity may enable new biomarkers and NK-targeted therapies to improve long-term graft survival.