Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses

Abstract

The X-chromosome-encoded transcription factor Foxp3 is thought to play a key role in the immune response as a regulator of the differentiation and suppressor function of regulatory T cells (Treg cells). Zheng et al. show here that regulatory T cells express the transcription factor IRF4 (interferon regulatory factor-4), which is essential for the differentiation of TH2 effector cells, and that IRF4 expression is dependent on Foxp3. IRF4 depletion in Treg cells induces TH2-driven autoimmune disease, leading the authors to suggest that IRF4 directs a module within Treg cells which selectively suppressesTH2 responses. This paper shows that regulatory T (Treg) cells express the transcription factor IRF4, which is essential for the differentiation of TH2 effector cells. IRF4 depletion in Treg cells induces TH2-driven autoimmune disease, leading the authors to suggest that IRF4 directs a module within Treg cells that selectively suppresses TH2 responses. In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of TH1, TH2 or TH17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (Treg). Treg cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented TH1 and TH2 cytokine production1,2,3. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets4,5. Here we show that in mouse Treg cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for TH2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows Treg cells with the ability to suppress TH2 responses. Indeed, ablation of a conditional Irf4 allele in Treg cells resulted in selective dysregulation of TH2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking Treg cells. Our results indicate that Treg cells use components of the transcriptional machinery, promoting a particular type of effector CD4+ T cell differentiation, to efficiently restrain the corresponding type of the immune response.