THU0048 1,25(OH)2D3 Inhibits Th17 Polarization and RORC Expression Through GATA3-Dependent and -Independent Mechanisms

Background Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). Regulation of Th17 cell activity is an important mechanism by which vitamin D exerts these effects. Aside from inhibiting Th17 cytokines and the Th17 transcription factor Rorγt, vitamin D induces IL-4 and GATA3. Interestingly, GATA3 over-expression inhibits experimental Th17-mediated autoimmunity. Objectives We studied the contribution of GATA3 in vitamin D-mediated suppression of Th17 polarization. Methods CD4+ T cells were sorted from patients with early RA, naïve DBA-1 mice, DBA-1 mice immunized with collagen type II (CII) or naïve CD2-GATA3 transgenic mice and cultured under T helper cell polarizing conditions with or without 1,25(OH)2D3, the active form of vitamin D. Results 1,25(OH)2D3 inhibits Th17 polarization in CD4+ cells from both non-immunized and CII-immunized mice, while up-regulating IL-4 and GATA3 expression. In these cultures, IL-4 inhibition partly reversed the vitamin D-mediated inhibition of Th17 polarization. Moreover, GATA3 over-expression reduces Th17 differentiation to a lower level than 1,25(OH)2D3. Interestingly, combining GATA3 over-expression and 1,25(OH)2D3 treatment reduced IL-17A and Rorγt expression even further. Furthermore, gene-expression analysis showed that NFAT-C2, which is involved in IL-17A production, was down-regulated by 1,25(OH)2D3. In addition, in T cells from patients with RA, 1,25(OH)2D3 inhibited Th17 cytokine and RORγt expression and induced IL-4 and GATA3 expression. Conclusions These data show that vitamin D-mediated regulation of Th17 polarization occurs through GATA3-dependent mechanisms, including direct effects on RORγt expression and IL-4-mediated inhibition of Th17 polarization. Moreover, GATA3-independent mechanisms are involved that may include modulation of NFAT-C2 expression. Disclosure of Interest None Declared