Novel Foxo1-dependent transcriptional programs control Treg cell function

Abstract

Regulatory T (Treg) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses1–4. Foxp3 operates as a late-acting differentiation factor controlling Treg cell homeostasis and function5, whereas the early Treg-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors6–10. However, whether Foxo proteins act beyond the Treg-cell-commitment stage to control Treg cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulatorof Treg cell function. Treg cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with Treg-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of Treg cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt–Foxo1 signalling module controls a novel genetic program indispensable for Treg cell function.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…Removal of this regulation in T Reg cells with PTEN deficiency results in severely compromised T Reg cell stability and in their conversion into inflammatory T H 1 and T H 17 cells 79,80 . Dampened AKT activity in T Reg cells supports the expression of IL-2 receptor α-chain (IL-2Rα; also known as CD25) and the nuclear localization of forkhead box O (FOXO) transcription factors, both of which are crucial for preventing T Reg cell plasticity towards inflammatory programmes [79][80][81] . Additionally, neuropilin 1, a receptor that is highly expressed by mouse tT Reg cells, recruits PTEN to the immunological synapse and blocks the activation of AKT during TCR stimulation, thus promoting T Reg cell stability and function 82 .…”

Excessive expression of miR-27 impairs Treg-mediated immunological tolerance

“…While most research efforts to date on miR-27 have been primarily focused on its role in tumorigenesis and embryonic stem cell differentiation (23)(24)(25)(26), many miR-27 targets identified in those studies such as FOXO1, runt-related transcription factor 1 (RUNX1), and SMAD2/3 were known to regulate Treg biology as well (27)(28)(29)(30)(31)(32). We found that, while FOXO1 did not seem to be repressed by miR-27 in T cells, markedly diminished SMAD2/3 and RUNX1 protein levels were detected in T cells that overexpressed miR-27 (Supplemental Figure 6).…”

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

“…Taken together, these data indicate that AnxA1 does not directly induce differentiation of niT cells, but it may facilitate the transfer of neutrophil-derived signaling proteins necessary for niT-cell formation. The transcription factor FOXO1 is the master regulator necessary for FOXP3 expression in inducible Tregs (34)(35)(36). Intriguingly, FOXO1 is expressed by neutrophils, where it is endowed with proapoptotic functions (37).…”