These results are intriguing because they suggest that sensitization with allergens may block IFN-α secretion during viral infections. Moreover, Gill et al.76 demonstrated that IgE, but not IgG, cross-linking significantly reduced IFN-α secretion from pDCs in response to both influenza A and B virus infection. Collectively, these results
demonstrate that pDCs from patients with asthma secrete significantly less IFN-α, and IgE cross-linking blocks IFN-α secretion even in pDCs from healthy controls in response to influenza virus, suggesting both an intrinsic and HIF-1 activation extrinsic mechanism for IFN-α suppression. Hence, IFN-α/β seems to be a key focal point of reciprocal antagonism by antiviral and allergic responses. As mentioned earlier, IFN-α/β promotes IL-21 secretion, which is reported to negatively regulate both IgE production
and allergic rhinitis.78–80 These findings are supported by early studies demonstrating that IFN-α/β can suppress C646 IgE class switching during B-cell priming.81,82 In summary, IFN-α/β may prove to be a potent cross-regulatory signal to block Th2/Th17 development as well as IgE production, which underscores its potential therapeutic use in atopic diseases. The role of IFN-α/β in modulating CD4+ Th responses is summarized in Fig. 1. In CD4+ T cells, IL-12 dominates as a unique signal driving effector Th1 commitment in both mice and humans.26,40,41 Although IFN-α/β may play ancillary roles in effector Th1 commitment, the two signals are not redundant. However, this division of labour may not be so distinct in CD8+ T cells, particularly in the mouse. Both IL-12 and IFN-α/β
have been reported to enhance CD8+ T-cell Methocarbamol effector activity. One of the first studies examining the role of IL-12 in CD8+ T-cell effector function concluded that neither IFN-γ secretion nor cytolytic activity was regulated by IL-12.83 This study also demonstrated that STAT4 knock-out CD8+ T cells could become functional effector cells, albeit to a lesser extent than wild-type cells. However, Mescher and colleagues84–87 have recently proposed that both IL-12 and IFN-α/β can act as a ‘third signal’ to promote both IFN-γ secretion and expression of perforin and granzymes in murine CD8+ cells. Furthermore, both IL-12 and IFN-α/β were found to markedly enhance cytolytic activity, and these effects were dependent upon STAT4.86 Based on these observations, it was concluded that IL-12 and IFN-α/β shared redundant roles in the regulation of CD8+ development and effector function. Interferon-α/β can play a significant role in priming effector responses and maintaining pools of memory cells via indirect actions through other cytokines and by enhancing antigen presentation. For example, IFN-α/β can act indirectly on innate cells to elicit IL-15 secretion, and perhaps IL-15 alone or in combination with IFN-α/β can drive homeostatic proliferation and maintenance of memory CD8+ T cells in vivo.