Oligodeoxynucleotides with CpG motifs (CpG ODN) mimic microbial DNA and activate effectors of innate immunity including NK cells. Human + ˇT cells (V + 9/V ˇ2) are antigen specific "natural memory" T cells in a preactivated stage, which respond to common nonprotein phosphoantigens. Among several CpG ODN tested, distinct CpG ODN sequences characterized by inducing high amounts of IFN- § /-g in PBMC elicited strong + ˇT cell and NK cell responses, as determined by CD69 expression, IFN-+ production, perforin content and lytic activity. These CpG ODN activated + ˇT cells and NK cells in the absence of an additional stimulus and synergistically increased responsiveness to cell-type-specific antigens like isopentenylpyrophosphate for + ˇT cells and NK-sensitive tumor cells for NK cells. NK cells and + ˇT cells were activated via IFN- § /-g released by CpG ODN-stimulated PBMC. Purified + ˇT cells and NK cells did not respond to CpG ODN but to recombinant IFN- § /-g . In conclusion, CpG ODN sequences were identified which, based on their ability to induce high amounts of IFN- § /-g , represent strong adjuvants for "natural memory" cells including responses of + ˇT cells to non-protein antigens. Early IFN- § /-g dependent stimulation of IFN-+ synthesis in NK cells and + ˇT cells may contribute to the CpG ODN-induced Th1 bias of an evolving immune response.