IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences

Abstract

IntroductionImmunostimulatory sequences (ISS) are short oligonucleotides (ODNs) that mimic the innate immune response to microbial DNA. 1 ISS contain one or more cytosine-phosphate-guanine (CpG) dinucleotide-containing motifs with unmethylated cytosine residues and are recognized by Toll-like receptor-9 (TLR-9), one of a family of receptors prominent in innate responses to microbial pathogens. 2,3 TLR-9 expression is not widely distributed, and ISS-responsive cells in human peripheral blood mononuclear cells (PBMCs) are limited to B cells and plasmacytoid dendritic cells (PDCs). ISS activate B cells to proliferate, secrete interleukin (IL)-6, and differentiate to plasma cells. 4 PDCs respond to ISS by secreting type I interferons, tumor necrosis factor ␣ (TNF-␣), and, upon signaling through CD40, IL-12. 2,5 In both cell types, ISS are potent enhancers of antigen-presenting cell (APC) function and induce key costimulatory molecules, such as CD40, CD80, and CD86. 6 In mixed cell populations, such as human PBMCs, the direct response to ISS initiates a cascade of secondary responses, including activation of macrophages and natural killer (NK) cells and the induction of interferon ␥ (IFN-␥) and a wide range of other cytokines and chemokines characteristic of inflammatory responses. [6][7][8][9][10] At least 3 classes of ISS can be distinguished on the basis of both structure and function. Uniformly modified phosphorothioate (PS) ISS, called CpG-B, strongly activate B cells but are weak stimulators of IFN-␣ from human PBMCs. Phosphodiester (PO)-linked sequences flanked by PS-linked poly-G ends, called CpG-A ISS, in contrast, are potent inducers of IFN-␣ and IFN-␥ but are weak activators of B cells. 11 Recently, a third class of ISS has been defined, called CpG-C. CpG-C ISS retain distinctive properties of both CpG-A and -B ISS with respect to IFN-␣ production and B-cell activation. 6 Preliminary data have shown that ISS affect PDC survival, maturation, and cytokine production, but the differential properties of these ISS on PDCs are otherwise undefined. 5,6,12 The efficient activation of APCs and induction of IL-12, IFN-␣, and IFN-␥ explains the potent ability of ISS to act as a strong T-helper cell 1 (Th)1-polarizing adjuvant. 13 Besides inducing Th1 responses, administration of ISS mixed or covalently linked to antigens can inhibit Th2 responses 14-17 and stimulate CD8 T-cell responses. 7 These activities have stimulated much interest in the clinical use of ISS as a vaccine adjuvant and in the treatment of allergy, asthma, cancer, and infectious diseases, and clinical trials are currently being conducted in all of these disease areas.IL-10 is a potent anti-inflammatory cytokine that can act as a feedback regulator of the inflammatory response to many microbial stimuli. 18 IL-10 can be produced by a number of different cell types and can inhibit both Th1 and Th2 responses by affecting APC function and dendritic cell (DC) maturation. 18-20 IL-10 inhibits activation and induces death of PDCs in vitro and can reduce PDC...

Interleukin‐10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA

“…IL-10-deficient mice are highly sensitive to systemically administrated LPS [11] and IL-10 also inhibits the TLR9 response to bacterial DNA or CpG oligonucleotides [18], [19].…”

Inhibitors of TLR-9 Act on Multiple Cell Subsets in Mouse and Man In Vitro and Prevent Death In Vivo from Systemic Inflammation

“…B cells and PDC, the two cell types in human blood that express TLR-9, can be inhibited with IRS in response to ISS activation despite their very different responses to ISS activation. Human B cells proliferate and produce the cytokines IL-6 and IL-10, whereas PDC will respond with a vigorous production of IFN-␣ (17,24). The different classes of ISS will also trigger very different quantitative responses in these cell subsets.…”

“…In human peripheral blood, B cells and PDCs are the two main subsets of cells that express TLR-9, although ISS elicit quite different cytokine responses from each. In response to ISS stimulation, B cells secrete proinflammatory cytokines such as IL-6, whereas PDCs secrete predominantly IFN-␣ (4,17,24). In addition, when stimulated with ISS and CD40L, PDC can produce moderate amounts of IL-12 (17,25).…”

“…In response to ISS stimulation, B cells secrete proinflammatory cytokines such as IL-6, whereas PDCs secrete predominantly IFN-␣ (4,17,24). In addition, when stimulated with ISS and CD40L, PDC can produce moderate amounts of IL-12 (17,25). We stimulated PDCs with the three different classes of ISS (CpG-A, -B, and -C) and IRS at a 1:1 ratio (Fig.…”

Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy

“…The reason for the lack of secretion of IFN-a may be owing to the inhibitory effect by IL-12 in the pDCs. 61 Although IL-10 regulated pDC activation in the tumor microenvironment, it did not inhibit the subsequent T-cell-priming ability of pDCs activated by AS Bcl-2 ODNs. The activation of CD4 þ T cells produces IFN-g, which activates CD8 þ T cells for an adaptive immune response.…”