Low vitamin D is associated with an increased risk of autoimmune diseases, whose pathology might involve TReg and Th17 dysregulation. Thus, understanding how vitamin D modifies CD4+ T-cell responses holds therapeutic potential. I therefore investigated the effect of 1,25(OH)2D3, the active form of vitamin D, upon human CD4+ T-cell differentiation. 1,25(OH)2D3, acted directly upon human CD4+ T-cells, suppressing inflammatory cytokines (IL-17, IL-21, IFNy and IL-22) whilst enhancing regulatory markers (CTLA-4, CD25, FoxP3 and IL-10). Consistently, 1,25(OH)2D3-treated T-cells suppressed division of naive T-cells stimulated by dendritic cells (DCs). Strong up-regulation of CTLA-4 by 1,25(OH)2D3reduced B7 expression by DCs, suggesting that enhanced CTLA-4 could be important mechanistically in 1,25(OH)2D3modified immunity. Furthermore, pro-regulatory effects of 1,25(OH)2D3were maintained under inflammatory conditions and modest suppression of established IL-17 by 1,25(OH)2D3 was observed, supporting ability of 1,25(OH)2D3to control T-cell phenotype at inflammatory sites. DCs could also efficiently convert 25(OH)D3to drive 1,25(OH)2D3-modified T-cell responses, which might be important in-vivo, given the low level of 1,25(OH)2D3in serum. Whether dysregulation of the TReg/T17 balance or response to 1,25(OH)2D3 was associated with disease outcome in early synovitis patients was also studied. Although the TReg/T17 ratio did not stratify with outcome, T-cell responses to 1,25(OH)2D3 were observed in all patients, suggesting that their VDR signalling is intact and that 1,25(OH)2D3might be useful in the treatment of synovitis