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Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells

Nature Immunology volume 12, pages 544–550 (2011)Cite this article

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Abstract

The molecular mechanisms that underlie T cell quiescence are poorly understood. Here we report that mature naive CD8+ T cells lacking the transcription factor Foxp1 gained effector phenotype and function and proliferated directly in response to interleukin 7 (IL-7) in vitro. Foxp1 repressed expression of the IL-7 receptor α-chain (IL-7Rα) by antagonizing Foxo1 and negatively regulated signaling by the kinases MEK and Erk. Acute deletion of Foxp1 induced naive T cells to gain an effector phenotype and proliferate in lympho-replete mice. Foxp1-deficient naive CD8+ T cells proliferated even in lymphopenic mice deficient in major histocompatibility complex class I. Our results demonstrate that Foxp1 exerts essential cell-intrinsic regulation of naive T cell quiescence, providing direct evidence that lymphocyte quiescence is achieved through actively maintained mechanisms that include transcriptional regulation.

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Figure 1: Foxp1-deficient mature naive CD8+ T cells gain effector phenotype and function and proliferate in response to IL-7 in vitro.
Figure 2: Foxp1 represses IL-7Rα expression in T cells.
Figure 3: Foxp1 represses Il7r expression by binding to its enhancer, and the downregulation of IL-7Rα expression in Foxo1-deficient T cells is Foxp1 dependent.
Figure 4: Foxp1-deficient CD8+ T cells with higher expression of IL-7Rα proliferate more in response to IL-7.
Figure 5: MEK-Erk activation is enhanced in Foxp1-deficient T cells, and blocking MEK activation inhibits the proliferation of Foxp1-deficient naive CD8+ T cells in response to IL-7 in vitro.
Figure 6: Foxp1-deficient mature naive T cells gain effector phenotype and function and proliferate in intact recipient mice.
Figure 7: Foxp1-deficient naive CD8+ T cells proliferate in sublethally irradiated mice deficient in H2-Kb and H2-Db.

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Acknowledgements

We thank R.A. DePinho (Harvard Medical School) for Foxo1f/f mice; W. Pear (University of Pennsylvania) for the retroviral vector MigR1-GFP; N.A. Speck (University of Pennsylvania) for the retroviral vector MigR1-Cre-GFP; E. Pure and J.R. Conejo-Garcia for critical reading of the manuscript; A.J. Caton and A. Bhandoola for discussions; J.S. Faust, D.E. Ambrose and D.J. Hussey for technical help with flow cytometry; and M.S. Wright, M. Houston-Leslie and D. DiFrancesco for help at the Animal Facility of the Wistar Institute. Supported by the National Institutes of Health (1K22AI070317-01A1 to H.H.), American Cancer Society (114937-IRG-96-153-07-IRG to H.H.) and the Wistar Cancer Center (P30 CA10815).

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  1. Jessica Willen

    Present address: Present address: Cedars-Sinai Medical Center, Los Angeles, California, USA.,

  2. Xiaoming Feng and Haikun Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. The Wistar Institute, Philadelphia, Pennsylvania, USA

    Xiaoming Feng, Haikun Wang, Hiroshi Takata, Timothy J Day, Jessica Willen & Hui Hu

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Contributions

X.F., H.W. and H.H. designed the experiments; H.W. and X.F. did the phenotypic and functional analysis of Foxp1f/fCre-ERT2+RosaYFP T cells in vitro; X.F. did all analyses of IL-7R expression, EMSA, in vitro proliferation of T cells from various Il7r+/− mice, mixed–bone marrow chimeras and cell transfer into mice deficient in H-2Kb and H-2Db with some help from H.T. and T.J.D.; H.W. did all retroviral infections, ChIP, cell signaling, immunoblot analysis, analysis of Foxp1f/fFoxo1f/f T cells and cell transfer into intact recipient mice with some help from H.T. and T.J.D.; H.T. did the phenotypic analysis of the Il7r+/− mice; T.J.D. did all mouse breeding with help from J.W.; H.H. conceived of the research, directed the study and provided overall supervision; and X.F., H.W., T.J.D. and H.H. prepared the manuscript. Authors with equal contributions are listed in alphabetical order.

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Correspondence to Hui Hu.

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Feng, X., Wang, H., Takata, H. et al. Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells. Nat Immunol 12, 544–550 (2011). https://doi.org/10.1038/ni.2034

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