The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has potent immunomodulatory properties that have promoted its potential use in the prevention and treatment of infectious disease and autoimmune conditions. A variety of immune cells, including macrophages, dendritic cells and activated T cells express the intracellular vitamin D receptor (VDR) and are responsive to 1,25(OH)2D3. Despite this, how 1,25(OH)2D3 regulates adaptive immunity remains unclear, and may involve both direct and indirect effects on the proliferation and function of T cells. To further clarify this issue we have assessed the effects of 1,25(OH)2D3 on human CD4+ CD25− T cells. We observed that stimulation of CD4+ CD25− T cells in the presence of 1,25(OH)2D3 inhibited production of pro-inflammatory cytokines including IFN- γ, IL-17 and IL-21 but did not substantially affect T cell division. In contrast to its inhibitory effects on inflammatory cytokines, 1,25(OH)2D3 stimulated expression of high levels of CTLA-4 as well as FoxP3, the latter requiring the presence of IL-2. T cells treated with 1,25(OH)2D3 could suppress proliferation of normally responsive T cells indicating that they possessed characteristics of adaptive Tregs. Our results suggest that 1,25(OH)2D3 and IL-2 have direct synergistic effects on activated T cells, acting as potent anti-inflammatory agents and physiologic inducers of adaptive Tregs.

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Regulatory T cells (Treg) are important in maintaining tolerance to self tissues. As both CD28 and CTLA-4 molecules are implicated in the function of Treg, we investigated the ability of their two natural ligands, CD80 and CD86, to influence the Treg-suppressive capacity. During T cell responses to alloantigens expressed on dendritic cells, we observed that Abs against CD86 potently enhanced suppression by CD4+CD25+ Treg. In contrast, blocking CD80 enhanced proliferative responses by impairing Treg suppression. Intriguingly, the relative expression levels of CD80 and CD86 on dendritic cells are modulated during progression from an immature to a mature state, and this correlates with the ability of Treg to suppress responses. Our data show that CD80 and CD86 have opposing functions through CD28 and CTLA-4 on Treg, an observation that has significant implications for manipulation of immune responses and tolerance in vivo.