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Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells

Nature Immunology volume 10, pages 504–513 (2009)Cite this article

Abstract

Foxo transcription factors regulate cell cycle progression, cell survival and DNA-repair pathways. Here we demonstrate that deficiency in Foxo3 resulted in greater expansion of T cell populations after viral infection. This exaggerated expansion was not T cell intrinsic. Instead, it was caused by the enhanced capacity of Foxo3-deficient dendritic cells to sustain T cell viability by producing more interleukin 6. Stimulation of dendritic cells mediated by the coinhibitory molecule CTLA-4 induced nuclear localization of Foxo3, which in turn inhibited the production of interleukin 6 and tumor necrosis factor. Thus, Foxo3 acts to constrain the production of key inflammatory cytokines by dendritic cells and to control T cell survival.

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Figure 1: Foxo3-deficient mice show no spontaneous T cell activation.
Figure 2: Foxo3 regulates the magnitude of an LCMV-induced immune response.
Figure 3: Foxo3Kca mice have more DCs and greater activation of DCs.
Figure 4: Greater immunogenicity of LCMV-infected Foxo3-deficient DCs.
Figure 5: Enhanced T cell responses induced by Foxo3Kca BMDCs.
Figure 6: IL-6 synthesis by Foxo3-deficient DCs is involved in enhanced T cell survival.
Figure 7: Production of IL-6 and TNF by stimulated DCs is inhibited by CTLA-4–Ig stimulation in a Foxo3-dependent way.

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Acknowledgements

We thank J.P. Allison (Sloan-Kettering Memorial Hospital) and J.A. Bluestone (University of California at San Diego) for CTLA-4-specific blocking antibodies; A. Brunet (Stanford University) for Foxo3-specific antibody; L. Lefrançois (University of Connecticut Health Center) for OVA-expressing vesicular stomatitis virus; L. Mack and E. Zuniga for assistance with virus titers; and M. Niwa for microscope facility use. Supported by the American Cancer Society (R.A.D.), the Robert A. and Renee E. Belfer Institute for Innovative Cancer Research (R.A.D.), the US National Cancer Institute (R.A.D.), the Division of Biological Sciences of the University of California, San Diego (S.M.H.) and the Fondation pour la Recherche Médicale (A.S.D.).

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Author notes

  1. Daniel R Beisner & Diego H Castrillon

    Present address: Present addresses: Genetics Institute of the Novartis Foundation, San Diego, California, USA (D.R.B.) and Department of Pathology, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, USA (D.H.C.).,

Authors and Affiliations

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

    Anne S Dejean, Daniel R Beisner, Irene L Ch'en, Yann M Kerdiles, Anna Babour & Stephen M Hedrick

  2. Ludwig Institute for Cancer Research, University of California, San Diego School of Medicine, La Jolla, California, USA

    Karen C Arden

  3. 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, Massachusetts, USA

    Diego H Castrillon & Ronald A DePinho

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Contributions

D.R.B. initiated the project and did lymphocyte characterization and LCMV infection under the supervision of S.M.H.; A.S.D. designed and did the remaining experiments in collaboration with D.R.B., I.L.C., Y.M.K. and S.M.H.; A.B. provided expertise in fluorescence microscopy analysis; R.A.D. and D.H.C. produced Foxo3−/− mice and provided intellectual input on the data; K.C.A. provided Foxo3Kca mice; S.M.H. initiated the project with input from R.A.D. and K.C.A. and supervised the experiments; and A.S.D. and S.M.H. wrote the manuscript with editorial and intellectual contributions from the other authors.

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Correspondence to Stephen M Hedrick.

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Dejean, A., Beisner, D., Ch'en, I. et al. Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells. Nat Immunol 10, 504–513 (2009). https://doi.org/10.1038/ni.1729

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