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

Abstract

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.

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Figure 1: Ablation of IRF4 in T reg cells results in autoimmune lymphoproliferative disease.
Figure 2: Increased numbers and activation of CD4 + T cells in mice harbouring IRF4-deficient T reg cells.
Figure 3: IRF4 deficiency in T reg cells results in a selective failure to control T H 2 responses.
Figure 4: Increased serum IgG1 and IgE concentration, germinal centre formation, and plasma cell tissue infiltration caused by IRF4 deficiency in T reg cells.
Figure 5: IRF4 interacts with Foxp3 and diminished expression of a subset of suppressor effector and T H 2 specific genes in IRF4-deficient T reg cells.

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Acknowledgements

We thank K. Hilgner and K. Murphy for providing TH1, TH2 and TH0 gene expression data sets, B. Sullivan, R. Locksley, S. Quezada and J. Allison for critical reagents, K. Forbush and L. Karpik for expert technical assistance and mouse colony management, and R. Dalla-Favera for discussions. This work was supported by grants from the National Institutes of Health (A.Y.R.). Y.Z .and J.M.K. were supported by the CRI-Irvington Institute postdoctoral fellowship. A.Y.R. is an investigator with the Howard Hughes Medical Institute.

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Correspondence to Alexander Y. Rudensky.

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Zheng, Y., Chaudhry, A., Kas, A. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458, 351–356 (2009). https://doi.org/10.1038/nature07674

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