Pathway of human Th17 differentiation. IL-17 producing CD4+ T helper (Th17) cells originate in presence of IL-23 and IL-1β, each of which upregulates orphan retinoid nuclear receptor (ROR)γt, T box expressed in T cells (T-bet), IL-23 receptor (IL-23R) and IL-12 receptor (IL-12R) in the naïve T hlper (Th) cell. When the two cytokines are produced in combination, IL-17 mRNA is also expressed and IL-17 is produced alone or in combination with IFN-γ. The presence of IL-12, in absence of IL-1β and IL-23, shifts the differentiation of the naïve Th cell toward the Th1 phenotype. IL-4, which is produced by the Th naïve cell itself following interaction of its Notch receptors with Jagged-1 expressed on the dendritic cell (DC) and/or by the presence of IL-25 (still unclear in humans), has a potent inhibitory effect on the expression of RORγt, T-bet, IL-23R, IL-12R, IFN-γ, and IL-17. Transforming growth factor (TGF)-β strongly inhibits the development of both Th1 and Th2 cells, whereas it has little or no effect on the development of Th17, thus indirectly favouring their expansion. Double parallel lines across the arrows mean inhibitory effect.
Romagnani Arthritis Research & Therapy 2008 10:206 doi:10.1186/ar2392