Recently a subset of interleukin (IL)-17-producing T cells (TH17), which are distinct from TH1 or TH2 cells, was described and shown to have a crucial role in the induction of autoimmune tissue injury. Th17 differentiation is accomplished by three overlapping steps: Induction, Amplification and Stabilization mediated by distinct cytokines. Whereas TGF-b+ IL-6 or IL-1 + IL-6 induces them, IL-21 amplifies Th17 cells, IL-23 stabilizes the phenotype of Th17 cells. Loss of any of the cytokines (TGF-β, IL-1, IL-6, IL-21 or IL-23) in the pathway results in a defect in generation of Th17. However not all Th17 cells are pathogenic and induce autoimmunity, IL-23 is a key cytokine that induces pathogenicity in Th17 cells (Lee et al., 2012). Using expression profiling at very high temporal resolution, novel computational algorithms and innovative nano-wire based “knock-down” approaches, we have developed a regulatory network that governs the development of Th17 cells. In addition to high-density temporal microarray analysis, we have performed single-cell RNA-seq of Th17 cells in order to characterize cellular heterogeneity, identify subpopulations, functional states and learn how gene expression variation affects Th17 effector functions. We have identified novel regulators of Th17 cells both in vivo and in vitro that do not affect Th17 differentiation but affects pathogenic vs. non-pathogenic functional states of Th17 cells. One of regulators CD5L (CD5like), produced in a soluble form by nonpathogenic Th17 cells, makes homo and heterodimers. Soluble forms of CD5L regulate differentiation of Th17 cells and inhibit development of autoimmunity and tissue inflammation.