The role of 1a,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL-10+CD4+T cells

1a,25-Dihydroxyvitamin D3 (1a25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1a25VitD3 promotes human and murine IL-10-secreting CD4+ T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3+ regulatory T (Treg) cells. 1a25VitD3 increased the frequency of both Foxp3+ and IL-10+ CD4+T cells in vitro. However, Foxp3 was increased at high concentrations of 1a25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3+ and IL-10+ T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1a25VitD3 is impaired by IL-10. 1a25VitD3 enables the selective expansion of Foxp3+ Treg cells over their Foxp3- T-cell counterparts. Equally, 1a25VitD3 maintains Foxp3+ expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4+Foxp3+ T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1a25VitD3 enhances the frequency of both IL-10+ and Foxp3+ Treg cells. In a translational setting, these data suggest that 1a25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.