Multiple effects of immunostimulatory DNA on T cells and the role of type I interferons

In addition to stimulating antigen-specific immune responses, infectious agents cause nonspecific activation of the innate immune system, notably up-regulation of costimulatory/adhesion molecules on APCs and cytokine production. In recent years it has become apparent that stimulation of the immune system by microorganisms is a property of a number of different cellular components, including DNA. As discussed earlier and elsewhere in this volume, the DNA of infectious agents--and indeed of all non-vertebrates tested--differs from mammalian DNA in being enriched for unmethylated CpG motifs. With appropriate flanking sequences, CpG DNA and synthetic CpG ODNs cause strong activation of APCs and other cells. In this article we have focussed on the capacity of CpG DNA/ODNs to alter T cell function. Whether these compounds act directly on T cells or function indirectly by activating other cells, especially APCs, is controversial [7, 8, 13, 14]. In contrast to other workers [8], we have yet to find definitive evidence that CpG DNA/ODNs can provide a co-stimulatory signal for purified T cells subjected to TCR ligation ([14] and unpublished data of authors). For this reason we lean to the notion that CpG DNA/ODNs modulate T cell function by inducing activation of APC rather than by acting directly on T cells. When injected in vivo in the absence of specific antigen, CpG DNA/ODNs have two striking effects on T cells, namely (1) induction of overt activation (proliferation) of memory-phenotype CD8+ cells, and (2) partial activation of all T cells, including naïve-phenotype T cells. Both actions of CpG DNA/ODNs are heavily dependent on the production of IFN-I by APC. For memory-phenotype (CD44hi) CD8+ cells, neither CpG DNA nor IFN-I can cause proliferation of purified APC-depleted T cells in vitro. Hence, under in vivo conditions, CpG DNA-induced proliferation of CD44hi CD8+ cells is probably mediated through the production of a secondary cytokine, i.e., by a cytokine that is directly stimulatory for CD44hi CD8+ cells. Based on the available evidence, it is highly likely that the effector cytokine is IL-15. With this assumption, our current model is that proliferation of CD44hi CD8+ cells induced by injection of CpG DNA/ODNs reflects production of IFN-I which, in turn, leads to synthesis of IL-15. Which particular cell types produce these two cytokines is unclear, although APCs are probably of prime importance. In addition to inducing proliferation of memory-phenotype