Regulation of cytokine production in human T helper cells
Research area: Cellular Immunology
Group leaders: Federica Sallusto
Status: In progress
In a previous study, we found that while human resting Th17 clones produced high amounts of IL-17, day 5-activated clones strongly downregulated IL-17 production. At later time points the clones gradually regained the capacity to produce IL-17 as the cells reverted to the resting state. The analysis of transcription factors showed that on day 2 and 5 following restimulation, Th17 clones downregulated RORC mRNA expression. In addition, while both resting and day 5 restimulated Th17 clones phosphorylated STAT3 in response to IL-6, only restimulated clones phosphorylated STAT5 in response to IL-2, consistent with the increased expression of CD25. Overexpression of RORgt significantly restored IL-17 production in activated Th17 clones, and restimulation in the presence of a STAT5 inhibitor rescued RORC mRNA expression and IL-17 production in a proportion of clones. Collectively, these data suggest that in activated human Th17 cells decreased RORgt expression and increased pSTAT5 - which may compete with pSTAT3 for binding to the IL17 locus - contribute to the transient downregulation of IL-17 production. Currently, we are extending these studies in two directions. On the one hand we are analyzing Th1 and Th2 clones to understand whether also in these cells cytokine production can be regulated by the activation state of the cell. On the other, we are dissecting the network of signals to find mechanisms of regulation of cytokine gene expression.