Activation of the immune system by bacterial CpG-DNA

Abstract

The past decade has seen a remarkable process of refocusing in immunology. Cells of the innate immune system, especially macrophages and dendritic cells, have been at the centre of this process. These cells had been regarded by some scientists as non-specific, sometimes perhaps even confined to the menial job of serving T cells by scavenging antigen and presenting it to the sophisticated adaptive immune system. Only over the last few years has it become unequivocally clear that cells of the innate immunity hold, by variation of context and mode of antigen presentation, the power of shaping an adaptive immune response. The innate immune response, in turn, is to a significant degree the result of stimulation by so-called pathogen-associated molecular patterns (PAMPs). One compound with high stimulatory potential for the innate immune system is bacterial DNA. Here we will review recent evidence that bacterial DNA should be ranked with other PAMPs such as lipopolysaccharide (LPS) and lipoteichoic acid. We will further review our present knowledge of DNA recognition and DNA-dependent signal transduction in cells of the immune system.

Figure 1

Model of cellular signalling by CpG-DNA. CpG-DNA (either as a free molecule or encapsulated in whole bacteria) is taken up by an immune cell, for instance a dendritic cell (DC). After processing through a chloroquine-sensitive pathway, signalling starts by engagement of toll-like receptor 9 (TLR9). The proteins myeloid differentiation factor 88 (MyD88), interleukin-1 receptor-associated kinase (IRAK) and tumour necrosis factor receptor-associated factor 6 (TRAF6) activate cellular kinases such as IκB-kinase (IKK) and mitogen-activated protein kinase (MAPK), and signal transduction on these well-known pathways leads to gene induction and evokes effector functions such as cytokine secretion. An alternative or parallel pathway (see the text for details) has been suggested to involve the activation of DNA-PKcs by direct, cytoplasmic binding of CpG-DNA, leading to IKK activation and nuclear factor (NF)-κB induction.