Pathogenic Th17 Cells Determinant in the Differentiation of Glycogen Synthase Kinase-3 Is an Early

CD4 + T cells are critical for host defense but are also major drivers of immune-mediated diseases. The classical view of Th1 and Th2 subtypes of CD4 + T cells was recently revised by the identification of the Th17 lineage of CD4 + T cells that produce IL-17, which have been found to be critical in the pathogenesis of autoimmune and other diseases. Mechanisms controlling the differentiation of Th17 cells have been well described, but few feasible targets for therapeutically reducing Th17 cells are known. The generation of Th17 cells requires IL-6 and activation of STAT3. During polarization of CD4 + T cells to Th17 cells, we found that inhibition of glycogen synthase kinase-3 (GSK3) blocked IL-6 production, STAT3 activation, and polarization to Th17 cells. Polarization of CD4 + T cells to Th17 cells increased by 10-fold the expression of GSK3b protein levels in Th17 cells, whereas GSK3b was unaltered in regulatory T cells. Diminishing GSK3 activity either pharmacologically or molecularly blocked Th17 cell production, and increasing GSK3 activity promoted polarization to Th17 cells. In vivo inhibition of GSK3 in mice depleted constitutive Th17 cells in intestinal mucosa, blocked Th17 cell generation in the lung after Francisella tularensis infection, and inhibited the increase in spinal cord Th17 cells and disease symptoms in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. These findings identify GSK3 as a critical mediator of Th17 cell production and indicate that GSK3 inhibitors provide a potential therapeutic intervention to control Th17-mediated diseases. C D4 + T cells are critical for host defense but are also major drivers of immune-mediated diseases. The classical division of CD4 + Th cells into IFN-g–producing Th1 and IL-4–producing Th2 subtypes was recently revised by the identification of the IL-17–producing lineage of Th17 cells (1, 2). Th17 cells have been found to be critical in the pathogenesis of auto-immune diseases and to be essential in clearing foreign pathogens (3). The transcription factors retinoid-related orphan receptor g T (RORgT) (4) and STAT3 (5, 6) direct Th17 differentiation from naive CD4 + T cells upon stimulation with TGF-b and in-flammatory cytokines IL-6 (7) or IL-21 (8, 9). Th17 cells are expanded and stabilized by IL-23 (10, 11) and predominantly produce the cytokines IL-17A, IL-17F, IL-21, and IL-22. In healthy mammals, Th17 cells are rarely detected except in the intestinal lamina propria, where they constitute a considerable proportion of the CD4 + T cells …