NK cells promote adaptive immune responses through their production of type 1 and type 2 cytokines or chemokines. Secretion of these factors by activated NK cells influences the differentiation of B and T lymphocytes. Increasing evidence indicates that NK cells are also directly involved in dendritic cell (DC) maturation. By contrast, a potential role for direct cell-cell interactions between NK and T lymphocytes, in particular CD4(+) T cells, has not been explored. We provide evidence that activated human NK cells are able of promoting TcR-dependent proliferation of resting autologous peripheral blood CD4(+) T cells by a process that involves costimulatory molecules of the immunoglobulin (Ig) and tumor necrosis factor (TNF) superfamilies. These findings suggest a novel link between natural and adaptative immune responses.