Oligodeoxynucleotides lacking CpG dinucleotides mediate Toll-like receptor 9 dependent T helper type 2 biased immune stimulation.
Oligodeoxynucleotides (ODN) with unmethylated CpG dinucleotides mimic the immune stimulatory activity of bacterial DNA in vertebrates and are recognized by Toll-like receptor 9 (TLR9). It is also possible to detect immune activation with certain phosphorothioate sequences that lack CpG motifs. These ODN are less potent than CpG ODN and the mechanism by which they stimulate mammalian leucocytes is not understood. We here provide several lines of evidence demonstrating that the effects induced by non-CpG ODN are mediated by TLR9. First, non-CpG ODN could not stimulate cytokine secretion from the splenocytes of TLR9-deficient (TLR9(-/-)) mice. Second, immunization of TLR9(+/+) but not TLR9(-/-) mice with non-CpG ODN enhanced antigen-specific antibody responses, although these were T helper type 2 (Th2)-biased. Third, reactivity to non-CpG ODN could be reconstituted by transfection of human TLR9 into non-responsive cells. In addition, we define a new efficient immune stimulatory motif aside from the CpG dinucleotide that consists of a 5'-TC dinucleotide in a thymidine-rich background. Non-CpG ODN containing this motif induced activation of human B cells, but lacked stimulation of Th1-like cytokines and chemokines. Our study indicates that TLR9 can mediate either efficient Th1- or Th2-dominated effects depending on whether it is stimulated by CpG or certain non-CpG ODN.
Vollmer
Jörg
J
Coley Pharmaceutical, Langenfeld, Germany. jvollmer@coleypharma.com
Weeratna
Risini D
RD
Jurk
Marion
M
Samulowitz
Ulrike
U
McCluskie
Michael J
MJ
Payette
Paul
P
Davis
Heather L
HL
Schetter
Christian
C
Krieg
Arthur M
AM
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D002455:Cell Division / Q000276:immunology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007372:Interferons / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D009841:Oligonucleotides / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D013936:Thymidine / Q000276:immunology; D051217:Toll-Like Receptor 9
C408982:CPG-oligonucleotide; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D007372:Interferons; D013936:Thymidine