The molecular mechanisms through which IRF4 can influence the development of Tc9 and Th9 cells seem to be very similar. Thus,

like in Th9 cells, IRF4 is essential for IL-9 expression in Tc9 cells and binds to the Il9 promoter (author’s unpublished data). Moreover, in Irf4–/– Tc9 cells, the expression of FOXP3 was found to be elevated and retroviral overexpression of FOXP3 suppressed IL-9 production in WT Tc9 cells [63]. Inhibition of IL-9 production by FOXP3 has also been shown in Th9 cells [29]. These data suggest that IRF4 regulates IL-9 production in Tc9 cells both directly via binding to the Il9 promoter and indirectly via affecting Apoptosis inhibitor FOXP3 expression (Fig. 2) [63]. Tc17 cells are characterized by the production of IL-17 and expression of the Tc17-specific transcriptional program including mRNAs for ROR-γt, RORα, IL-21, and IL-23 receptor (IL-23R) [64, 66, 73]. Tc17 cells have been identified in MS lesions [74]. Likewise, upon immunization with a truncated peptide from myelin oligodendrocyte glycoprotein (MOG37–50), WT mice suffer from EAE accompanied by increased numbers of IL-17-producing CD8+ T cells in the LNs and CNS [66]. By contrast,

Irf4–/– mice have been shown to be resistant to the induction of EAE and failed to develop IL-17-producing CD8+ T cells, illustrating the need for IRF4 not only for Th17-, but also for Tc17-cell differentiation in vivo. Also in vitro, IRF4 was required for the acquisition of the Tc17 phenotype: Irf4–/– CD8+ T cells failed to Selleckchem Dasatinib produce IL-17 upon culturing with TGF-β and IL-6 and expressed greatly diminished levels

of mRNAs characteristic of a Tc17-specific transcriptional program. Instead, under Tc17-inducing GBA3 conditions, Irf4–/– cells displayed enhanced expression of EOMES and FOXP3, which are master regulators of CTL and CD8+ Treg-cell differentiation, respectively. Forced expression of EOMES and FOXP3 additively inhibited IL-17 production by WT CD8+ T cells, illustrating that the high amounts of these transcription factors contribute to the altered phenotype of Irf4–/– CD8+ T cells. Thus, on the one hand, IRF4 acts as molecular activator of Tc17-cell differentiation by promoting expression of the master regulators ROR-γt and RORα, and on the other hand, IRF4 acts as suppressor of alternative CD8+ T-cell fates by downregulating the expression of EOMES and FOXP3 (Fig. 2) [24]. In addition, our data revealed that MOG37–50-induced EAE is mediated by reciprocal cooperation between IL-17A-producing Tc17 cells and CCR6-expressing Th17 cells [24]. Although WT CD8+ T cells that were transferred into Irf4–/– mice prior to EAE induction developed a Tc17-like phenotype, these cells failed to migrate into the CNS and to induce autoimmune inflammation. Help by CCR6-expressing Th17 cells was required to enable WT Tc17-cell-mediated CNS inflammation.