Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation

Abstract

During differentiation of naive CD4+ helper T (TH) cells into effector cells, specific cytokine gene loci undergo extensive changes in chromatin modification. A novel lineage of TH cells that is regulated by transforming growth factor-beta (TGFbeta) and interleukin-6 (IL-6) has been identified recently as promoting tissue inflammation. These inflammatory TH (THi) cells, also called TH17 or TH(IL-17), produce IL-17 and IL-17F, two highly homologous cytokines that have genes located in the same chromosomal region. Here, using chromatin immunoprecipitation techniques, we have demonstrated that similar to the regulation in TH1 and TH2 cell lineages, polarization of THi cells was accompanied by selective chromatin remodeling events. Histone H3 acetylation and Lys-4 tri-methylation were specifically associated with IL-17 and IL-17F gene promoters in THi lineage. At an early stage of T cell activation, histone acetylation on these promoters was greatly promoted by a combination of TGFbeta and IL-6, suggesting their synergistic role in initiating chromatin accessibility for transcription factors. Furthermore, we identified multiple noncoding sequences within the IL-17-IL-17F locus conserved across species. These elements were also associated with hyperacetylated histone 3 in a lineage-specific manner and may thus serve as potential regulatory regions. In summary, our results demonstrate for the first time that THi cell differentiation is associated with epigenetic changes in the IL-17-IL-17F locus, which suggests novel mechanisms in T cell functional regulation.