33,36,41,42 The in vitro differentiation studies described above can only address

issues of sufficiency for a cytokine to regulate the development of specific phenotypes. However, when assessed in vivo, IFN-α/β signalling seemed to contribute to Th1 development.43,44 Likewise, mice deficient in IL-12 were still able to generate Th1 cells in response to murine hepatitis virus infection, demonstrating that multiple pathways were involved and may be required for Th1 development.45 One possible pathway involves IL-18, which was shown to synergize with IFN-α/β to activate STAT4 in the absence of IL-12.46,47 Interferon-α/β also promotes the expression of IL-21 and the IL-21R in T cells.48 Panobinostat ic50 As IL-21 induces Th1-associated genes, possibly in synergy with IL-18, this may represent another pathway by which IFN-α/β contributes to Th1 development.49,50 Taken together, these studies suggest that while IFN-α/β is not sufficient to drive Th1 commitment via direct and sustained STAT4 activation, it contributes to Th1 responses in vivo by collaborating with other cytokines that are differentially induced in response to various classes of pathogens. Finally, IFN-α/β may play a broader role in CD4+ T-cell functions by check details regulating the development and stability of long-lived memory cells. Although IFN-α/β may promote

cell cycle arrest and, in some cases, apoptosis in certain cell types, CD4+ T cells respond quite differently depending upon their activation status. Marrack et al.51 demonstrated that IFN-α/β protected cells from undergoing acute activation-induced cell death. Though not directly driving proliferation, IFN-α/β seemed to block apoptosis following antigen stimulation in vitro, which may be related to the development of

long-lived central memory cells. As central memory cells were first described as having decreased effector capabilities, they display enhanced recall proliferation coincident with elevated secretion of IL-2.52 Recently, Davis et al.53 demonstrated a direct role for IFN-α/β in promoting the development of human central memory-like Staurosporine concentration CD4+ T cells and preserving elevated IL-2 expression preferentially within these cells versus their effector cell counterparts. Hence, IFN-α/β acts to prevent terminal differentiation of effector CD4+ T cells by selectively regulating IL-2 expression at the expense of driving inflammatory cytokine secretion. As IFN-α/β is induced during Th1-dominant antiviral immune responses, IFN-α/β production may act to suppress the development of other subsets and their associated effector functions. Indeed, a growing body of literature has highlighted the role of IFN-α/β in cross-regulating the differentiation and stability of both Th2 and Th17 cells. These two subsets are guided by distinct signals, with Th2 cells controlled by IL-4, and Th17 cells responding to transforming growth factor-β, IL-6 and IL-1β.