Nuclear receptor NR2F6, as a signal-induced functional switch, that safeguards Th17 cell effector functions. A schematic representation of signaling events in Th17 cells is shown: NR2F6 serves as a TCR/CD28 signaling threshold regulated barrier against autoimmunity where NR2F6 is part of a negative feedback loop that limits inflammatory tissue damage. In the absence of a strong antigenic signal, NR2F6 remains pre-bound to the signal response element (RE) and recruits co-repressors to suppress transcription of defined gene loci. In high-affinity antigen-stimulated T cells, however, NR2F6 is phosphorylated by PKC and, thereby, loses its DNA binding capacity; subsequently, NFAT and/or RORγt are able to bind to their promoter/enhancer sequences and recruit additional co-activators to activate transcription of, e.g., Il17a. In robustly activated CD4+ T cells, NFAT and AP-1 bind cooperatively to sites throughout the genome. Thus and intriguingly, NR2F6 emerges as a prototypical repressor that, in the absence of high affinity antigen receptor stimulation, “locks out” Th17 lineage programming. Because Th17 cell-intrinsic function of NR2F6 renders Th17 cells less pathogenic by repressing key cytokine transcription, NR2F6 agonists may provide a rational basis for the treatment of Th17-mediated autoimmune pathologies.