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

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Abstract
Foxo transcription factors influence a wide variety of cellular responses. Hedrick and colleagues show that dendritic cells express Foxo3 to suppress the production of interleukin 6 and prevent excessive accumulation of antigen-specific T cells. 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.