Microbial Recognition Via Toll-Like Receptor-Dependent and -Independent Pathways Determines the Cytokine Response of Murine Dendritic Cell Subsets to CD40 Triggering

Abstract

Dendritic cells (DC) can produce Th-polarizing cytokines and direct the class of the adaptive immune response. Microbial stimuli, cytokines, chemokines, and T cell-derived signals all have been shown to trigger cytokine synthesis by DC, but it remains unclear whether these signals are functionally equivalent and whether they determine the nature of the cytokine produced or simply initiate a preprogrammed pattern of cytokine production, which may be DC subtype specific. Here, we demonstrate that microbial and T cell-derived stimuli can synergize to induce production of high levels of IL-12 p70 or IL-10 by individual murine DC subsets but that the choice of cytokine is dictated by the microbial pattern recognition receptor engaged. We show that bacterial components such as CpG-containing DNA or extracts from Mycobacterium tuberculosis predispose CD8α+ and CD8α−CD4− DC to make IL-12 p70. In contrast, exposure of CD8α+, CD4+ and CD8α−CD4− DC to heat-killed yeasts leads to production of IL-10. In both cases, secretion of high levels of cytokine requires a second signal from T cells, which can be replaced by CD40 ligand. Consistent with their differential effects on cytokine production, extracts from M. tuberculosis promote IL-12 production primarily via Toll-like receptor 2 and an MyD88-dependent pathway, whereas heat-killed yeasts activate DC via a Toll-like receptor 2-, MyD88-, and Toll/IL-1R domain containing protein-independent pathway. These results show that T cell feedback amplifies innate signals for cytokine production by DC and suggest that pattern recognition rather than ontogeny determines the production of cytokines by individual DC subsets.

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

“…Furthermore, higher production of IL-6 was observed by CD8 -DC compared to CD8 + DC (97 vs. 19 pg/mL). These results are in line with previous reports [41][42][43], and indicate restricted cytokine production by CD8 -DC after recognition of yeast.…”

“…Furthermore, higher production of IL-6 was observed by CD8 -DC compared to CD8 + DC (97 vs. 19 pg/mL). These results are in line with previous reports [41][42][43], and indicate restricted cytokine production by CD8 -DC after recognition of yeast. Fungal stimulation of DC has been reported to lead to IL-23 production and subsequent activation of Th17 cells [42,44].…”

Newly Activated T Cells Promote Maturation of Bystander Dendritic Cells but Not IL-12 Production

“…It is becoming increasingly clear that not all aspects of DC activation are regulated concordantly and that they can be differentially induced by innate vs adaptive signals. For example, innate stimuli can promote production of cytokines such as IL-12, IL-10, or IFN-␣ whereas CD40 ligation cannot initiate cytokine synthesis but can amplify that which has been initiated by microbial signals (14,15). However, it is not clear whether other aspects of DC activation are similarly dependent on microbial priming and whether T cell-derived signals act exclusively on Ag-bearing DC or also regulate the function of bystander cells.…”

Identification and Characterization ofChlamydia pneumoniae-Specific Proteins That Activate Tumor Necrosis Factor Alpha Production in RAW 264.7 Murine Macrophages

“…It has previously been shown that TLRs mediate translation of microbial recognition into expression of specific subsets of chemokines and cytokines by macrophages and dendritic cells (6,21,53,54). Furthermore, TLR2 and TLR4 have been shown to induce different sets of chemokines and cytokines, implying that the innate immune response can be customized for different pathogens (11,15,39). Recent evidence has shown that C. pneumoniae activates the innate immune system via TLRs.…”