Dynamic regulatory network controlling TH17 cell differentiation

Abstract

Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The TH17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between TH17 and other CD4+ T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling TH17 cell differentiation. A global view of the genetic networks regulating the differentiation of TH17 cells is presented, based on temporal expression profiling, computational network reconstruction and validation of predicted interactions by nanowire-mediated siRNA perturbation. This paper presents a global view of the gene networks regulating interleukin-17-producing helper T (TH17) cell differentiation. Transcriptional profiling, computational algorithms and a novel technique using silicon nanowires to manipulate genes in primary T cells, are used to build a detailed picture of the complex network that controls TH17 differentiation and keeps the pro-inflammatory potential of TH17 cells in check. The study identifies and validates 39 regulatory factors and highlights novel drug targets for controlling TH17 cell differentiation. Elsewhere in this issue, two groups present the surprising finding that increased salt concentrations promote autoimmune disease by stimulating the production of TH17 cells from CD4+ T cells.