The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells

Abstract

Regulatory T cells (Treg cells) are required for peripheral tolerance. Evidence indicates that Treg cells can adopt specialized differentiation programs in the periphery that are controlled by transcription factors usually associated with helper T cell differentiation. Here we demonstrate that expression of the transcription factor Blimp-1 defined a population of Treg cells that localized mainly to mucosal sites and produced IL-10. Blimp-1 was required for IL-10 production by these cells and for their tissue homeostasis. We provide evidence that the transcription factor IRF4, but not the transcription factor T-bet, was essential for Blimp-1 expression and for the differentiation of all effector Treg cells. Thus, our study defines a differentiation pathway that leads to the acquisition of Treg cell effector functions and requires both IRF4 and Blimp-1.

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Figure 1: Expression of Blimp-1 in a subset of Treg cells.
Figure 2: Blimp-1-expressing Treg cells have an effector phenotype, produce IL-10 and localize to mucosal sites.
Figure 3: Blimp-1 is dispensable for the generation of effector Treg cells but is required for their IL-10 production and tissue homeostasis.
Figure 4: Blimp-1 limits numbers of Treg cells and is induced by IL-2 and inflammatory signals.
Figure 5: IRF4 is required for the generation of Blimp-1-expressing effector Treg cells, but T-bet is not.
Figure 6: Blimp-1 and IRF4 jointly regulate the effector Treg cell differentiation program.
Figure 7: Binding of IRF4 and Blimp-1 to regulatory regions in the Il10 and Ccr6 loci.

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Acknowledgements

We thank T. Mak, L. Wu, J. Altin and P. Bouillet for mice; S. Sterle, N. Bernard, R. Thong and K. Elder for technical support; Y. Zhan, I. Campbell and K. Shortman for antibodies; L. Corcoran and D. Tarlinton for discussion and reagents; and Y. Zheng and A. Rudensky for the full microarray data set already published in part17. Supported by the National Health and Medical Research Council of Australia (E.C., G.T.B., S.L.N. and A.K.), L'Oréal Australia For Women in Science Fellowship (E.C.), the Swiss National Science Foundation (F.M.), the Viertel Foundation, the Howard Hughes Medical Institute (G.T.B.), the Pfizer Australia Research Fellowship program (S.L.N.), the Leukemia & Lymphoma Society (A.K.), Boehringer Ingelheim (Busslinger group) and the European Union Sixth Framework Programme FP6 (EuTRACC project, Busslinger group).

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E.C., A.X., M.M., F.M., M.M. and A.K. designed and did experiments; W.S. and G.K.S. analyzed the microarray data; G.T.B. and M.B. designed experiments; and S.L.N. and A.K. designed experiments and wrote the paper and contributed equally to this work.

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Correspondence to Stephen L Nutt or Axel Kallies.

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Supplementary Figures 1–12, Supplementary Tables 1–2 and Supplementary Methods (PDF 2066 kb)

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Cretney, E., Xin, A., Shi, W. et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 12, 304–311 (2011). https://doi.org/10.1038/ni.2006

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