The mechanism for this defect

has not been described. If IL-12 negatively regulates memory cell development while IFN-α/β positively regulates this process, it remains puzzling how memory cells develop when both of these cytokines are secreted during intracellular pathogen infections. In mice, both IL-12 and IFN-α/β are sufficient to promote effector function in CD8+ T cells when activated in vitro, albeit IFN-α/β is not quite as potent as IL-12 in regulating cytokine expression.86,101 However, there seems to be less redundancy between Raf inhibitor these two cytokine pathways in driving human CD8+ T-cell effectors. Recently, Ramos et al.102 compared the ability of IL-12 and IFN-α to promote cytokine secretion and lytic activity in primary naive human CD8+ T cells. In contrast to mouse, IL-12 induced robust lytic activity and secretion of IFN-γ and tumour necrosis factor-α, but treatment with IFN-α alone had little effect on these activities compared with cells activated under neutralizing conditions. Two recent studies claim that IFN-α enhances IFN-γ production103 and granzyme expression104 in human CD8+ T cells, but those reports

only compared IFN-α to neutralizing conditions. Indeed, IFN-α does marginally increase IFN-γ production over the baseline control, but this level is still 10-fold less than the magnitude of production induced by IL-12.102 Consequently, IL-12 appears to be the main signal driving the expression of effector Protein Tyrosine Kinase inhibitor cytokines. However, while IFN-α failed to regulate effector cell development, IFN-α enhanced the development of CD8+ central memory (TCM) cells.102 This activity was unique to IFN-α, because IL-12 promoted only effector cell (TEM) but not TCM development. These cells lack immediate effector function but rapidly acquire these responses following secondary stimulation, hence representing

a functional memory population. Interestingly, when naive cells receive signals from both IL-12 and IFN-α, both TEM and TCM cells develop simultaneously, and they are derived from subpopulations of cells that differentially progress through Pregnenolone cell division. The IL-12 programmes TEM phenotypes in actively dividing cells, whereas IFN-α induces TCM development by limiting proliferation and terminal differentiation in a subset of cells. These points are summarized in Fig. 2. Regarding the mechanism of this developmental programme, Ramos et al.102 demonstrated that the development of distinct effector and memory phenotypes of human CD8+ T cells occurred through the reciprocal regulation of their respective cytokine receptors. Development of TCM was regulated by marked induction of the IFNAR with low expression of the IL-12R, whereas effector cells rapidly divided and progressively lost IFNAR while gaining IL-12R expression.