1,25-Dihydroxyvitamin D3 and IL-2 Combine to Inhibit T Cell Production of Inflammatory Cytokines and Promote Development of Regulatory T Cells Expressing CTLA-4 and FoxP3

Abstract

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.

Vitamin D and the Regulation of Placental Inflammation

“…In view of the well-recognized ability of 1,25 (OH) 2 D 3 to promote transition from Th1 cell activity to more tolerant Th2 cell responses (28), it is tempting to speculate that loss of 1,25(OH) 2 D 3 synthesis by the placenta may contribute to a less favorable immune environment during pregnancy. Moreover, recent reports demonstrating direct effects of 1,25(OH) 2 D 3 on the generation of regulatory T cells (29) suggest that impaired synthesis of this hormone in the placenta may have wider consequences for tolerogenic immune responses during pregnancy, even in the absence of an immune challenge. IL-10 is produced by regulatory T cells and other cells (including villous cytotrophoblasts) within the placenta, where it appears to function as a key facilitator of successful pregnancy (30).…”

Vitamin D and immune function: an overview

“…Treatment of naive CD4 + T-cells with 1,25(OH) 2 D potently induces the development of Treg (112) , and this may exert beneficial effects in autoimmune disease and host-graft rejection (113)(114)(115) . Although, 1,25(OH) 2 D can stimulate Treg development directly via VDR expression by CD4 + T-cells (116,117) , it may also act via effects on antigen-presenting cells. Specifically, as outlined earlier, the ability of 1,25(OH) 2 D to induce an immature DC phenotype will promote tolerogenic Treg activity in CD4 + T-cells (118)(119)(120) .…”

Single-Nucleotide Polymorphism at CYP27B1-1260, but Not VDR Taq I, Is Possibly Associated with Persistent Hepatitis B Virus Infection

“…However, different immunological mechanisms are involved in autoimmune disorders and nonautoimmune diseases such as viral infections. 1,25(OH) 2 D may suppress T helper-1 (Th1) and promote Th2 differentiation through action on CD4 + T cells (Rigby et al, 1987;Mü ller and Bendtzen, 1992;Boonstra et al, 2001) and when combined with interleukin (IL)-2, can directly suppress the production of proinflammatory cytokines IFN-g, IL-17, and IL-21 and promote development of regulatory T cells expressing cytotoxic T lymphocyte antigen-4 and FoxP3 ( Jeffery et al, 2009). …”