066 Glucocorticoids promote intrinsic human Th17 differentiation

Although Th17 cells are critical to host protection at epithelial barriers, they can play a pathogenic role in inflammatory and autoimmune diseases. Glucocorticoids (GC) are therapeutically used to suppress undesired inflammation, but the common persistence or even increase of Th17 responses in GC-treated patients led us to investigate the effect of GC on Th17 development. We found that GC trigger a Th17 differentiation program in naïve human CD4 T cells in the absence of antigen-presenting cells or exogenous cytokines. GC-induced Th17 cells expressed IL-10 and their development was associated with an inhibition of Th2, and particularly Th1 differentiation. GC induction of Th17 differentiation was not linked to increased IL-1β, IL-6 and TGF-β, yet GC downregulated IL-2. Consistently, the addition of exogenous IL-2 prevented the GC-induced increase in Th17/Th1 ratios. Also, IL-2/IL-2R blocking enhanced Th17/Th1 ratios, altogether suggesting a mechanistic role for IL-2 regulation in GC-induced Th17 polarization. Functionally, supernatants of GC-differentiated T cells were superior to those of non-GC-differentiated T cells at inducing antimicrobial peptides and pro-IL-1β in keratinocytes, despite decreased IFN-γ and increased IL-10. Finally, GC also favored Th17 over Th1 among memory T cells from blood and skin. Altogether, our data define GC as human Th17 polarizing factors.