Accordingly, IL-9 production by Th9 cells strictly correlated with IRF4 expression, and Irf4–/– CD4+ T cells failed to differentiate into IL-9 producers under Th9-inducing conditions [44]. Conversely, transient deletion of IRF4 in wild-type (WT) CD4+ T cells prevented the differentiation of Th9 cells. At the molecular level, IRF4 directly induced IL-9 expression by binding to and activating the Il9 promoter. The importance of IRF4 for Th9 development in vivo was shown in a mouse model for allergic asthma, in which Irf4–/– mice were totally resistant to the induction of allergic airway disease. Importantly, reconstitution of the mice with WT Th9 cells restored asthma symptoms, demonstrating not only

the importance of IRF4 for PLX4032 nmr Th9 development in vivo, but also PXD101 in vivo a role for Th9 cells during allergic airway disease [44]. Consistent with the finding that AICEs are present in the upstream regulatory elements of the Il9 and Il10 genes [16], BATF cooperates with IRF4 for the induction

of IL-9 [42]. Accordingly, mouse and human Th9 cells depend on BATF for IL-9 production. Similarly to IRF4, BATF expression in Th cells promotes allergic airway inflammation [42]. As Th9-cell differentiation was in addition described to depend on the ETS transcription factor PU.1 [45], IRF4 might also regulate Th9-cell differentiation via EICE binding in concert with PU.1. Finally, for the induction of IL-9 production, IRF4 cooperates with SMAD2 and SMAD3 proteins, which are induced by TGF-β signaling [21], indicating multiple mechanisms and interaction partners utilized by IRF4 during Th9-cell differentiation (Fig. 1A). The relevance of IRF4 for the in vivo development of Th17 cells has been demonstrated in several

autoimmune disease models, in which pathogenic Th17 cells play a central role. Irf4–/– mice have been shown to be totally resistant to the induction of experimental autoimmune encephalomyelitis (EAE), which is a mouse model for multiple sclerosis (MS), and this resistance correlated with lack of Th17-cell differentiation [46]. Reconstitution of Irf4–/– mice with WT CD4+ T cells restored Tideglusib their susceptibility to the disease and the transferred cells developed a Th17 phenotype, again pointing to a T-cell intrinsic defect of Irf4–/–CD4+ T cells [46]. Furthermore, IRF4 deficiency was protective in T-cell-dependent colitis models, such as transfer colitis and oxazolone-induced as well as trinitrobenzene sulfonic acid induced colitis [47]. Again, resistance to colitis induction correlated with defective differentiation of naïve Irf4–/–CD45RBhighCD4+ T cells into Th17 cells, along with reduced IL-6 production by Irf4–/– mucosal T cells. Consistent with these findings, IRF4 levels were augmented in patients with inflammatory bowel disease and correlated with enhanced production of IL17 and IL22 mRNA [47, 48]. Thus, lack of IRF4 seems to cause resistance to Th17-mediated autoimmune diseases.