Figure 1.

Alternative models for selective Th1/Th2 induction by DCs. (A) The maturation model, which posits that Th1 stimuli drive immature DCs (iDC) to develop into completely mature DCs (mDC) able to induce Th1 via signal 3 (e.g., IL-12) provision to T cells. In contrast, most Th2 stimuli elicit little or no activation, generating semimature DCs (sDC), which fail to provide signal 3. In the absence of complete DC maturation, responses default to the Th2 mode. Because EDN activates DCs (and their secretion of IL-12) while promoting Th2 induction, it does not fit into this scheme. (B) The alternate pathway model, in which Th1 and Th2 stimuli are linked to distinct sets of pattern recognition receptors (PRR), such as TLRs and CLRs. For example, strong signaling through TLRs initiates intracellular cascades, principally involving MyD88, which up-regulate proinflammatory cytokine production, including that of IL-12. In contrast, ligation with a CLR-binding, Th2-inducing stimulus can activate Syk in a pathway that favors IL-10 rather than IL-12, although no consequent signal 3 has been identified (reference 31). The outcome of exposure to complex antigens may depend on the relative strength of signal in two or more competing receptor-dependent pathways. (C) The inhibition model, in which signaling pathways may intersect and inhibit one another. For example, Th2 stimuli that up-regulate ERK phosphorylation and stabilize c-Fos effect an intracellular block on IL-12 production (reference 23). In a complementary fashion, strong TLR4 ligation can negate the ability of SEA to induce Th2 responses, though in this instance the signaling mechanism has yet to be defined (reference 32). The default model is unlikely to hold true in most in vivo Th2 settings, whereas a combination of the alternate pathway and inhibition models is perfectly plausible.