Preferential stimulation of human lymphocytes by oligodeoxynucleotides that copy DNA CpG motifs present in virulent genes of group A streptococci

Immunostimulatory oligodeoxynucleotides (ODN) containing CpG dinucleotides have been shown to stimulate murine and human lymphocytes. We investigated the presence of stimulatory DNA motifs in specific group A streptococcal (GAS) genes to elucidate the potential role of DNA in the immunopathogenesis of GAS infections. Despite low GC content in GAS DNA, the emm1 gene encoding the streptococcal M1 protein contained a relatively high frequency of TTCG(T/C), TCGTCG and (G/A)TCGT motifs that preferentially stimulated human lymphocytes. Interestingly, these motifs were also found in genes encoding M-like proteins of group C and G streptococci. ODN copying the emm1 gene sequences harboring these motifs induced the proliferation of human B cells and up-regulated the expression of CD25 on their surface. T cells were not required for the response to the ODN, indicating a direct effect of these motifs on B lymphocytes. Inter-individual variations in responsiveness to ODN were observed, suggesting that host factors potentiate these responses. The finding that GAS DNA contains stimulatory motifs that induce activation of human B cells in a T cell-independent manner suggests that this may be an important mechanism by which the bacteria can target the innate arm of the immune system in the early stages of invasive infections.