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.
Rothenfusser
S
S
Department of Internal Medicine, Division of Clinical Pharmacology, University of Munich, Munich, Germany.
Hornung
V
V
Krug
A
A
Towarowski
A
A
Krieg
A M
AM
Endres
S
S
Hartmann
G
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D016207:Cytokines; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D052899:Pore Forming Cytotoxic Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054353:Perforin; D016899:Interferon-beta; D007371:Interferon-gamma