Concomitant with the upregulation of IL-10 production, recently activated Th17 clones switched off IL-17 production that was regained only at later time points. Mechanistically,

the loss of IL-17 production was explained by the downregulation of RORγt in recently activated Th17 cells and by the induction, in response to autocrine IL-2, of phosphorylated STAT5, which competes with STAT3 for binding to the IL-17 promoter [49]. These studies reveal a novel aspect of Th17 biology, namely that IL-17 production is strongly elicited in effector and memory Th17 cells within a few hours after antigenic stimulation, while it is actively suppressed at later time points when anti-inflammatory mechanisms, such as the production of IL-10, are induced to prevent excessive immunopathology. Time- and activation-dependent regulation of cytokine gene Cabozantinib nmr expression selleck chemicals llc has been described in other cell types such as dendritic cells where different genes are activated with different kinetics over several hours after the initial stimulus [50].

In this context, human Th17 cells may provide an attractive model system to study the contribution of reversible and dynamic chromatic changes in T-cell activation [51]. In this review, we have discussed how the study of cytokine production, homing capacity, antigenic specificity, and activation state can be a useful approach to understand the complex physiology of effector and memory human T cells. We are starting to understand mechanistically some of this complexity, for instance in the Th17 field we are now appreciating the role of IL-1β and IL-12 in the induction of IL-17/IFN-γ double-producing T cells, a phenotype

that is frequently observed in pathological conditions. Furthermore, we are beginning to appreciate the role of the Th17-cell activation state and cytokine milieu in modulating inflammatory from and anti-inflammatory cytokine production. These findings thus reveal new targets and rationale for therapeutic intervention of inflammatory diseases. Several years ago, studies performed in the human system demonstrated that the vast majority of memory Th cells maintain both memory and flexibility of cytokine gene expression. For instance, Th1 and Th2 cells could be induced to simultaneously produce IFN-γ and IL-4 when stimulated in opposite polarizing conditions, that is, in the presence of IL-4 or IL-12, respectively [52]. At the time, the general consensus from mouse studies was that Th cells were undergoing a rapid and irreversible commitment to their lineage and that the silenced cytokine genes were repositioned to heterochromatin in order to maintain cell identity.