Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses (original) (raw)

• Letter
• Published: 01 February 2009
• Ashutosh Chaudhry1,2 nAff6,
• Arnold Kas1,2,
• Paul deRoos1,2 nAff6,
• Jeong M. Kim1,2,
• Tin-Tin Chu1,2,
• Lynn Corcoran4,
• Piper Treuting3,
• Ulf Klein5 &
• …
• Alexander Y. Rudensky1,2 nAff6

Nature volume 458, pages 351–356 (2009)Cite this article

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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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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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Author notes

1. Ye Zheng, Ashutosh Chaudhry, Paul deRoos & Alexander Y. Rudensky
   Present address: Present address: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.,

Authors and Affiliations

1. Howard Hughes Medical Institute,,
   Ye Zheng, Ashutosh Chaudhry, Arnold Kas, Paul deRoos, Jeong M. Kim, Tin-Tin Chu & Alexander Y. Rudensky
2. Department of Immunology,,
   Ye Zheng, Ashutosh Chaudhry, Arnold Kas, Paul deRoos, Jeong M. Kim, Tin-Tin Chu & Alexander Y. Rudensky
3. Department of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA,
   Piper Treuting
4. Immunology Division, The Walter and Eliza Hall Institute, Parkville Victoria 3050, Australia
   Lynn Corcoran
5. Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA,
   Ulf Klein

Authors

1. Ye Zheng
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2. Ashutosh Chaudhry
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3. Arnold Kas
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4. Paul deRoos
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5. Jeong M. Kim
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6. Tin-Tin Chu
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7. Lynn Corcoran
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8. Piper Treuting
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9. Ulf Klein
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10. Alexander Y. Rudensky
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Correspondence toAlexander 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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• Received: 18 February 2008
• Accepted: 21 November 2008
• Published: 01 February 2009
• Issue Date: 19 March 2009
• DOI: https://doi.org/10.1038/nature07674

Editorial Summary

T helper cells: IRF4 in control

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.