No abstract

SUMMARY Foxo transcription factors integrate extrinsic signals to regulate cell division, differentiation and survival, and specific functions of lymphoid and myeloid cells. Here we showed the absence of Foxo1 severely curtailed the development of Foxp3+ regulatory T (Treg) cells, and those that developed were nonfunctional in vivo. The loss of function included diminished CTLA-4 receptor expression as the Ctla4 gene was a direct target of Foxo1. T cell specific loss of Foxo1 resulted in exocrine pancreatitis, hind limb paralysis, multi-organ lymphocyte infiltration, anti-nuclear antibodies and expanded germinal centers. Foxo-mediated control over Treg cell specification was further revealed by the inability of TGF-β cytokine to suppress T-bet transcription factor in the absence of Foxo1, resulting in IFN-γ-secretion. In addition the absence of Foxo3 exacerbated the effects of the loss of Foxo1. Thus, Foxo transcription factors guide the contingencies of T cell differentiation and specific functions of effector cell populations.

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

In caspase 8-deficient mouse T cells, necroptosis occurs via a Ripk3- and Ripk1-dependent pathway independent of autophagy and programmed necrosis.

In this paper, the color coding of samples in Figures 3C, 3D, and 4A was incorrect in the version of the paper published online on January 6. CXCR3 À CCR6 À cells should be purple; CXCR3 À CCR6 + cells should be green. The figures have been corrected in the paper that is now online and in the print issue.