Natural killer (NK) cell infiltration of kidney allografts is a distinguishing feature of antibody-mediated rejection. Bailly et al. identify a distinct population of cytotoxic CD160 + interleukin-21 receptor + CD56 dim CD16 bright NK cells that are uniquely found in the peripheral blood of donor-specific antibody-positive kidney transplant recipients and are present in kidney allografts with active antibody-mediated rejection. This population is implicated in a T follicular helper/interleukin-21/NK cell axis that links donor-specific antibody generation with graft-infiltrating NK cells in antibody-mediated rejection.