Maintaining the Th17 phenotype in vitro requires a specific cytokine environment that includes IL-23 and IL-1 (26). IL-4R, those induced in vivo during AAD did not, possibly rendering them unresponsive to IL-4-induced signals. However, in vitro derived antigen-specific Th17 cells transferred in vivo to OVA and alum-sensitized mice also managed IL-17 secretion and did not produce option cytokines upon subsequent OVA challenge. Thus, although Th17 cells can adopt new phenotypes in response to some inflammatory environments, our data suggest that in allergic inflammation, Th17 cells are comparatively stable, and retain the potential to produce IL-17. This might reflect a cytokine environment that promotes Th17 stability, and allow a broader immune response at tissue barriers that are susceptible to allergic inflammation. Introduction Upon activation, na?ve CD4+ T cells differentiate into specific T helper lineages depending on the cytokines in the environment. IL-12 promotes the IFN–secreting Th1 phenotype, IL-4 induces the development of Th2 cells, which produce IL-4, IL-5, and IL-13 and the combination of IL-4 and TGF- promotes the development of IL-9-secreting Th9 cells (1C9). Together, IL-6, TGF-, IL-23 and IL-1 induce the development of IL-17-secreting Th17 cells (10C15). In addition to IL-17A and IL-17F, Th17 cells produce IL-21 and IL-22 and are important for immunity against extracellular bacteria and fungi, but also contribute to the pathology of autoimmune diseases and allergic inflammation (16C20). The Th17 effector program is induced by a network of transcription factors, which includes RORt and STAT3, and is negatively regulated by the Th1 and Th2/Th9-inducing cytokines, IFN- and IL-4, respectively (11, 21C25). T helper lineages were originally thought to have stable phenotypes, and once a T helper cell acquired the potential for secreting a particular cytokine, the cell was committed to this phenotype. However, experiments with Th17 cells exhibited that they had dramatic instability, defaulting to an IFN–secreting phenotype in vitro (25C28). Maintaining the Th17 phenotype in vitro requires a specific cytokine environment that includes IL-23 and IL-1 (26). The ability of a Th17 cell to acquire IFN–secreting potential requires IL-12-induced STAT4, and the induction of T-bet to repress Runx1 and IRF4 (25, 27, 29, 30). Th17 plasticity, the ability to acquire other T helper cell phenotypes, is usually reflected by the increased expression of a stem cell signature and bivalent chromatin marks at T helper lineage transcription factors that allow responsiveness to the cytokine environment (31C34). Although other T helper subsets have some plasticity, the dramatic instability of the Th17 phenotype suggests Diphenhydramine hcl that maintenance of IL-17-secreting cells might be detrimental to the host. The plasticity of the Th17 lineage in vivo was first shown in a series of studies where polyclonal populations, or Th17 cells purified on the basis of reporter expression, were adoptively transferred into mice with autoimmune Rabbit polyclonal to CUL5 diseases including colitis and type I diabetes, or lymphopenic Diphenhydramine hcl hosts (27, 35C37). These studies agreed with in vitro studies, and exhibited the acquisition of IFN–secreting potential following transfer. However, these studies did not exclude the possibility that some IL-17-unfavorable cells could have been transferred and expanded in vivo. The use of IL-17A and IL-17F lineage tracer mouse models allowed tracking of cells that formerly expressed IL-17, and confirmed the acquisition of a Th1-like phenotype by Th17 cells in vitro, and in vivo during the development of autoimmune disease (38, 39). In experimental autoimmune encephalomyelitis (EAE), the majority of IFN–secreting cells found in the CNS are former secretors Diphenhydramine hcl of IL-17A and IL-17F (38, 39). IL-17-secreting T cells can acquire other phenotypes as well. Th17 cells adopt a follicular helper T cell phenotype in Peyers patches inducing the development Diphenhydramine hcl of IgA-producing germinal center B cells and promoting gut homeostasis (40). Additionally, IL-17-secreting T cells can terminate IL-17 production without generating cytokines associated with other lineages. Upon clearance of acute cutaneous contamination with locus was used to generate a targeting vector that replaced the 3 end of exon 1 with an EGFP-Cre fusion protein and an recombinase gene inserted into the locus). gene inserted into the locus). values of 0.05 or less were considered as significant..