Abstract

The pleiotropic transcription factor IRF4 is shown to regulate CD4+ T-cell differentiation and TH17 function through cooperative binding interactions with BATF and JUN family proteins via AP1–IRF4 composite elements (AICEs). Kenneth Murphy and colleagues study the roles of the AP-1 transcription factor BATF in dendritic-cell differentiation — a process that primes CD8+ T-cell responses to intracellular pathogens — and provide evidence for molecular compensation by related family members. Compensation is based on the interaction of the BATF leucine-zipper domains with the interferon regulatory factors IRF4 and IRF8 to mediate cooperative gene activation. In a complementary study, Warren Leonard and colleagues provide evidence that IRF4 regulates CD4+ T-cell differentiation and TH17 function by cooperative binding interactions with the AP-1 family members BATF and JUN. These studies point to potential new targets for manipulating key immune responses that depend on BATF–IRF4 interactions. Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response1,2. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity3, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5′-GGAAnnGAAA-3′)1. Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5′-TGAnTCA/GAAA-3′) motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4−/− T cells and IRF4 binding was diminished in Batf−/− T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.