Abstract
Recognition of microbial products by germ-line-encoded PRR initiates immune responses, but how PRR mediate specific host responses to infectious agents is poorly understood. We and others have proposed that specificity is achieved by collaborative responses mediated between different PRR. One such example comprises the fungal β-glucan receptor Dectin-1, which collaborates with TLR to induce TNF production. We show here that collaborative responses mediated by Dectin-1 and TLR2 are more extensive than first appreciated, and result in enhanced IL-23, IL-6 and IL-10 production in DC, while down-regulating IL-12 relative to the levels produced by TLR ligation alone. Such down-regulation occurred with multiple MyD88-coupled TLR, was dependent on signaling through Dectin-1 and also occurred in macrophages. These findings explain how fungi can induce IL-23 and IL-6, while suppressing IL-12, a combination which has previously been shown to contribute to the development of Th17 responses found during fungal infections. Furthermore, these data reveal how the collaboration of different PRR can tailor specific responses to infectious agents.
Highlights
Recognition of microbial products by germ-line-encoded PRR initiates host immune responses
Signaling from Dectin-1 is sufficient for the induction of cytokines, such as IL-10 [10], but we speculated that these responses may be influenced by collaborative signaling with TLR2, such as we have previously documented for the induction of TNF [5]
As we reported previously [10], stimulation of these cells with purified b-glucan induced the production of IL-10 and this response was Dectin-1-dependent, as cells lacking this receptor did not respond to these carbohydrates (Fig. 1A)
Summary
Recognition of microbial products by germ-line-encoded PRR initiates host immune responses. Given that most TLR signal through a common adaptor MyD88, it is unclear how recognition of these structures can translate into specific responses required for effective host defense. We and others have proposed that the collaboration of different PRR induces specific host immune responses [2, 3]. Signaling through Dectin-1, which is largely mediated through Syk kinase, is thought to be sufficient for production of cytokines, such as IL-10, IL-6 and IL-23 [7, 8], whereas others, such as TNF, require the recognition of another undefined fungal component by TLR2, and signaling through the MyD88 pathway [5].
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