Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells

Abstract

Bacterial DNA and immunostimulatory (i.s.) synthetic CpG-oligodeoxynucleotides (ODN) act as adjuvants for Th1 responses and cytotoxic T cell responses to proteinaceous antigens. Dendritic cells (DC) can be referred to as "nature's adjuvant" since they display the unique capacity to sensitize naive T cells. Here, we demonstrate that bacterial DNA or i.s. CpG-ODN cause simultaneous maturation of immature DC and activation of mature DC to produce cytokines. These events are associated with the acquisition of professional antigen-presenting cell (APC) function. Unfractionated murine bone marrow-derived DC and FACS-fractionated MHC class IIlow (termed immature DC) or MHC class IIhigh populations (termed mature DC) were stimulated with bacterial DNA or i.s. CpG-ODN. Similar to lipopolysaccharide, i.s. CpG-ODN caused up-regulation of MHC class II, CD40 and CD86, but not CD80 on immature and mature DC. In parallel both DC subsets were activated to produce large amounts of IL-12, IL-6 and TNF-alpha. CpG-ODN-activated DC displayed professional APC function in allogeneic mixed lymphocyte reaction and in staphylococcal enterotoxin B-driven naive T cell responses. We interpret these findings to mean that bacterial DNA and i.s. CpG-ODN cause maturation (first step) and activation (second step) of DC to bring about conversion of immature DC into professional APC.

Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis

“…Unmethylated CpG motifs in bacterial DNA trigger an immune response characterized by the production of proinflammatory and Th1 cytokines (6)(7)(8)(9). This evolutionarily conserved response can protect the host from infectious pathogens (18)(19)(20), but it also increases the risk of developing autoimmune and inflammatory diseases (4,(21)(22)(23)(24).…”

“…Blinded histologic evaluation of joints 4 days after injection of CpG ODNs or bacterial DNA provides rigorous evidence of pathology, which correlates with joint swelling (Pearson's correlation coefficient r ϭ 0.59, P Ͻ 0.0001) (5). Although systemically administered CpG DNA stimulates B cells, natural killer cells, and dendritic cells to proliferate, mature, and/or secrete in vivo (6)(7)(8)(9), no direct effect on the joints has ever been reported (Table 1) (4). The findings of the present study demonstrate that the generalized immune activation triggered by systemic CpG ODN treatment increases host susceptibility to a subsequent arthritogenic stimulus.…”

“…Numerous studies have shown that CpG DNA has immunostimulatory properties, triggering immune cells to proliferate, mature, and secrete a variety of proinflammatory chemokines and cytokines (6)(7)(8)(9). This immune activation can be inhibited by "suppressive" ODNs, which block the production of Th1 and proinflammatory cytokines (10)(11)(12)(13).…”

The role of tissue macrophages in the induction of proinflammatory cytokine production following intravenous injection of lipoplexes

“…Dendritic cells in the spleen also might be closely involved in the cytokine production via a CpG motif-mediated mechanism. 36 Dendritic cells in the red pulp also have a high phagocytic activity, and lipoplexes accumulated in the red pulp. However, the effect of GdCl 3 on the functions of dendritic cells is unknown.…”

Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO

“…As a result, direct activation of DC by TLR9 signaling is a prerequisite for induction of full T cell function [6]. Activation of DC via TLR thus provides a link between innate and adaptive immunity [4,5,[7][8][9][10]. Therefore, CpG-ODN applied locally has been successfully used as an adjuvant for vaccination in animal models and clinical trials [11][12][13][14][15].…”