Long-Range Transcriptional Control of the Il2 Gene by an Intergenic Enhancer

Interleukin-2 (IL-2) is a potent cytokine with roles in both immunity and tolerance. Genetic studies in humans and mice demonstrate a role forIl2 in autoimmune disease susceptibility, and for decades the proximalIl2 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 theIl2 gene located 83 kb upstream of the transcription start site. This element can potently enhanceIl2 transcription in recombinant reporter assaysin vitro , and the native region undergoes chromatin remodeling, transcribes a bidirectional enhancer RNA, and loops to physically interact with theIl2 genein vivo in a CD28-dependent manner in CD4+ T cells. Thiscis 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 theIl2 locus is more complex than previously appreciated and suggest a novel molecular basis for the genetic association ofIl2 polymorphism with autoimmune disease.