Distinct CpG oligonucleotide sequences activate human gamma delta T cells via interferon-alpha/-beta.

Oligodeoxynucleotides with CpG motifs (CpG ODN) mimic microbial DNA and activate effectors of innate immunity including NK cells. Human gamma delta T cells (Vgamma9/Vdelta2) are antigen specific "natural memory" T cells in a preactivated stage, which respond to common non-protein phosphoantigens. Among several CpG ODN tested, distinct CpG ODN sequences characterized by inducing high amounts of IFN-alpha/-beta in PBMC elicited strong gamma delta T cell and NK cell responses, as determined by CD69 expression, IFN-gamma production, perforin content and lytic activity. These CpG ODN activated gamma delta T cells and NK cells in the absence of an additional stimulus and synergistically increased responsiveness to cell-type-specific antigens like isopentenylpyrophosphate for gamma delta T cells and NK-sensitive tumor cells for NK cells. NK cells and gamma delta T cells were activated via IFN-alpha/-beta released by CpG ODN-stimulated PBMC. Purified gamma delta T cells and NK cells did not respond to CpG ODN but to recombinant IFN-alpha/-beta. In conclusion, CpG ODN sequences were identified which, based on their ability to induce high amounts of IFN-alpha/-beta, represent strong adjuvants for "natural memory" cells including responses of gamma delta T cells to non-protein antigens. Early IFN-alpha/-beta dependent stimulation of IFN-gamma synthesis in NK cells and gamma delta T cells may contribute to the CpG ODN-induced Th1 bias of an evolving immune response.