Very interesting data published by Man et al. [22] suggest that IRF4 contributes to effector CD8+ T-cell differentiation by regulating metabolic pathways, in particular glycolysis. T cells need high energy supply for their strong proliferative burst after activation. To meet this demand, they switch their metabolism from oxidative phosphorylation to aerobic glycolysis [72]. This process seems to be greatly impaired in the absence of IRF4,

because activated Irf4–/– CD8+ T cells demonstrated lower uptake of glucose and produced less l-lactate as compared SB525334 molecular weight to WT CD8+ T cells. Moreover, oxygen consumption and extracellular acidification rate were lower in Irf4–/– as compared to WT CD8+ T cells. Consistently, the authors found direct binding of IRF4 to regulatory regions of genes encoding transcription factors that regulate cellular metabolism, including hypoxia-inducible factor α (HIF1α) and forkhead box O 1 (FOXO1), as well as of several genes encoding regulators of glycolysis such as the glucose transporters GLUT1 and GLUT3 [22]. However, it is still possible that the disturbed metabolic switch in Irf4–/–CD8+ T cells is secondary to their impaired expansion and effector differentiation, which is regulated by IRF4 by other means. Therefore, these attractive data need further evaluation, including

identification of the mechanisms through which IRF4 integrates strength of TCR ligation and metabolic pathways. Besides its requirement for effector CTL differentiation, IRF4 also participates in the formation of the memory Vemurafenib order CD8+ T-cell pool. In L. monocytogenes infected Irf4–/– mice, the numbers of antigen-specific memory CD8+ T cells and the production of the cytokines IFN-γ and TNF-α were significantly lower than those observed in L. monocytogenes infected WT mice [23]. Similarly in response to influenza MRIP infection, mice with conditional deletion of IRF4 in CD8+ T cells generated significantly lower numbers of antigen-specific memory cells [25]. Taken together, IRF4 is a fundamental regulator of effector and memory CTL formation by acting upstream of other transcription factors, including BLIMP-1 and T-BET (Fig. 2),

which regulate these processes, and by connecting the strength of TCR ligation to aerobic glycolysis. Similarly to Th9 cells, Tc9 cells produce the cytokines IL-9 and IL-10 upon in vitro induction, whereas expression of the Th2-cytokines IL-5 and IL-13 is strongly reduced as compared to Tc2 cells. In comparison to CTLs, Tc9 cells express diminished amounts of the transcription factors EOMES and T-BET and, accordingly, they display low cytotoxic activity in vitro [63, 68]. In adoptive T-cell transfer experiments, Tc9 cells showed IL-9-dependent antitumor activity [68]. In an allergic airway disease model, Tc9 cells alone were not pathogenic by themselves, but promoted airway inflammation when combined with Th2 cells [63].