Interleukin-2 (IL-2) is a potent cytokine with roles in both immunity and tolerance. Genetic studies in humans and mice demonstrate a role for Il2 in autoimmune disease susceptibility, and for decades the proximal Il2 upstream regulatory region has served as a paradigm of tissue-specific, inducible gene regulation. In this study, we have identified a novel long-range enhancer of the Il2 gene located 83 kb upstream of the transcription start site. This element can potently enhance Il2 transcription in recombinant reporter assays in vitro, and the native region undergoes chromatin remodeling, transcribes a bidirectional enhancer RNA, and loops to physically interact with the Il2 gene in vivo in a CD28-dependent manner in CD4(+) T cells. This cis regulatory element is evolutionarily conserved and is situated near a human single-nucleotide polymorphism (SNP) associated with multiple autoimmune disorders. These results indicate that the regulatory architecture of the Il2 locus is more complex than previously appreciated and suggest a novel molecular basis for the genetic association of Il2 polymorphism with autoimmune disease.
