The Il17a promoter and its regulation by orphan nuclear receptors. The interleukin (Il) 17a minimal promoter and conserved non-coding sequences (CNS) are controlled by the general transcriptional machinery and by several nuclear receptors. The DNA consensus binding sequences within the minimal and the CNS2 region of the Il17a promoter for NFAT and for nuclear receptors such as NR2F6 and RORγt are shown. Two orphan nuclear receptors, RORγt and NR2F6, thereby have key roles in Il17a gene regulation. Of note, NR2F-family members form homo- or hetero-dimers that interact with co-binding partners that are either co-activators or co-repressors. These complexes bind to their consensus sequences (HRE) in the DNA to either inhibit or stimulate target gene transcription. NR2F6 thereby plays a fundamental role in the CD4+ T cell compartment by balancing Th17 differentiation and inflammation, as do several other nuclear receptors such as the AHR, RARs, PPARs, LXR, VDR, GR and ER. The lineage-specific master transcription factor RORγt is the only nuclear receptor established to enhance Th17 differentiation and restrains iTregs.