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Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis

Nature Immunology volume 14, pages 230–237 (2013)Cite this article

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Abstract

Regulatory T cells (Treg cells) develop from progenitor thymocytes after the engagement of T cell antigen receptors (TCRs) with high-affinity ligands, but the underlying molecular mechanisms are still unclear. Here we show that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have essential roles in Treg cell development. Mice that lacked all Nr4a factors could not produce Treg cells and died early owing to systemic autoimmunity. Nr4a receptors directly activated the promoter of the gene encoding the transcription factor Foxp3, and forced activation of Nr4a receptors bypassed low-strength TCR signaling to drive the Treg cell developmental program. Our results suggest that Nr4a receptors have key roles in determining CD4+ T cell fates in the thymus and thus contribute to immune homeostasis.

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Figure 1: Compound deletion of all Nr4a receptors resulted in loss of Treg cells and systemic lethal autoimmunity.
Figure 2: Nr4a-TKO mice developed a TH2-type inflammation.
Figure 3: Mice deficient in both Nr4a1-Nr4a3 mice have fewer Treg cells and develop autoimmunity.
Figure 4: Redundancy among Nr4a factors in Foxp3 induction.
Figure 5: CD4+ T cell–intrinsic defect in the Treg cell development of Nr4a-TKO cells.
Figure 6: Activation of Nr4a compensates for suboptimal TCR signaling strength in thymic Treg cell development.

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Acknowledgements

We thank N. Shimizu, S. Tsuruta, N. Shiino, Y. Noguchi and M. Asakawa for technical assistance, and Y. Ushijima for manuscript preparation. Foxp3-hCD2-hCD52-KI mice were originally from the laboratory of S. Hori (Research Center for Allergy and Immunology, RIKEN), and the Nr4a1fl/fl and Nr4a2fl/fl mice were from H. Ichinose (Tokyo Institute of Technology). Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Japan Society of the Promotion of Science, the Takeda Science Foundation, the Uehara Memorial Foundation, Mochida Memorial Foundation and the SENSHIN Medical Research Foundation.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

    Takashi Sekiya, Ikkou Kashiwagi, Rei Yoshida, Tomohiro Fukaya, Rimpei Morita, Akihiro Kimura & Akihiko Yoshimura

  2. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan

    Hiroshi Ichinose

  3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France

    Daniel Metzger & Pierre Chambon

  4. Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan

    Akihiko Yoshimura

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Contributions

T.S. and A.Y. designed the research and analyzed data; T.S., I.K., R.Y., T.F., A.K. and R.M. did the experiments; H.I., D.M. and P.C. provided the Nr4a2fl and Nr4a1fl mouse strain, plasmids and feedback on the manuscript; and T.S. and A.Y. wrote the manuscript.

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Correspondence to Takashi Sekiya or Akihiko Yoshimura.

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Sekiya, T., Kashiwagi, I., Yoshida, R. et al. Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat Immunol 14, 230–237 (2013). https://doi.org/10.1038/ni.2520

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