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Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor

Nature Immunology volume 10, pages 176–184 (2009)Cite this article

Abstract

Foxo transcription factors have a conserved role in the adaptation of cells and organisms to nutrient and growth factor availability. Here we show that Foxo1 has a crucial, nonredundant role in T cells. In naive T cells, Foxo1 controlled the expression of the adhesion molecule L-selectin, the chemokine receptor CCR7 and the transcription factor Klf2, and its deletion was sufficient to alter lymphocyte trafficking. Furthermore, Foxo1 deficiency resulted in a severe defect in interleukin 7 receptor α-chain (IL-7Rα) expression associated with its ability to bind an Il7r enhancer. Finally, growth factor withdrawal induced a Foxo1-dependent increase in Sell, Klf2 and Il7r expression. These data suggest that Foxo1 regulates the homeostasis and life span of naive T cells by sensing growth factor availability and regulating homing and survival signals.

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Figure 1: Foxo1 is preferentially expressed in lymphoid cells.
Figure 2: Foxo1 is required for maintenance of T cell homeostasis.
Figure 3: Foxo1 is dispensable for T cell development.
Figure 4: Foxo1 regulates L-selectin, CCR7 and Klf2 expression and T cell homing in vivo.
Figure 5: Foxo1 is required for naive T cell survival.
Figure 6: Foxo1 is required for IL-7Rα expression in naive T cells and binds to an Il7r enhancer.
Figure 7: Foxo1-mediated control of Il-7Rα and trafficking receptors after cell starvation.

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Acknowledgements

We thank W. D'Souza and M. McGargill for discussions and assistance with adoptive transfer experiments; T. Ludwig (Columbia University) for ERCre mice; C. Murre (University of California at San Diego) for PTENf/f-ERCre mice; H. Cheroutre (La Jolla Institute for Allergy and Immunology) for Il7r−/− mice; S. Kaech for identifying the evolutionarily conserved regions of Il7r; and A. Goldrath and P. Marrack for critical reading of the manuscript. Supported by funds made available by the University of California, San Diego Division of Biological Sciences.

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Authors and Affiliations

  1. Division of Biological Sciences, and Department of Cellular and Molecular Medicine, Molecular Biology Section, University of California, San Diego, 92093-0377, California, USA

    Yann M Kerdiles, Daniel R Beisner, Roberto Tinoco, Anne S Dejean & Stephen M Hedrick

  2. Departments of Adult Oncology, Center for Applied Cancer Science, Belfer Institute for Innovative Cancer Science, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Diego H Castrillon & Ronald A DePinho

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Contributions

Y.M.K. designed and conducted all of the experiments, in collaboration with D.R.B., R.T. and A.S.D. The breeding and initial characterization of the Foxo1; Cd4Cre mice were carried out by D.R.B. and R.T. Mice with a loxP-targeted Foxo1 locus were produced by D.H.C. and R.A.D. S.M.H. initiated the project with R.A.D. and supervised the experimentation. Y.M.K. and S.M.H. wrote the manuscript with contributions from the other authors.

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Correspondence to Stephen M Hedrick.

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Kerdiles, Y., Beisner, D., Tinoco, R. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol 10, 176–184 (2009). https://doi.org/10.1038/ni.1689

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