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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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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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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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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DOI: https://doi.org/10.1038/ni.1729
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