Interactions of 1α,25-dihydroxyvitamin D3 with IL-12 and IL-4 on cytokine expression of human T lymphocytes

Background: 1 alpha,25-Dihydroxy vitamin D3 (1 alpha,25[OH](2)D-3) exerts its effects on the immune system, particularly through suppression of T helper/cytotoxic cell 1 (T-H/T(C)1)-mediated reactions, although direct actions of 1 alpha,25(OH)(2)D-3 on human T lymphocytes have not yet been studied in detail. Objective: We evaluated the effect of 1 alpha,25(OH)(2)D-3 on basal and cytokine-driven T-cell functions at the single-cell level. Methods: We used 4-color flow cytometry for simultaneous detection of intracellular cytokines in CD4+ and CD8+ human PBMCs that had been cultured in the presence of 1 alpha,5(OH)(2)D-3 singly or in combination with either IL-12 or IL-4. According to the exploratory nature of these investigations, the Bonferroni correction was not applied for data analysis and presentation. Results: 1 alpha,25(OH)(2)D-3 had little effect on T-H/T(C)1 cytokines but significantly inhibited IL-12-induced IFN-gamma production. Constitutive synthesis of T-H/T(C)2-related cytokines was also only modestly affected by 1 alpha,25(OH)(2)D-3 alone. When T-H/T(C)2 differentiation was induced by IL-4, 1 alpha,25(OH)(2)D-3 significantly expanded the percentages of IL-4(+) and IL-13(+) cells. However, the predominant effect of 1 alpha,25(OH)(2)D-3 on T lymphocytes, particularly in the presence of IL-4, was the induction of separate CD4(+) and CD8(+) subpopulations with almost exclusive expression of IL-6. This might be an important facet of the immunomodulatory action of 1 alpha,25(OH)(2)D-3 because IL-6 might act in parallel with 1 alpha,25(OH)(2)D-3 in modulation of T-H/T-C effector cell functions. Conclusions: Our data imply that the specific actions of 1 alpha,25(OH)(2)D-3 on cytokine-stimulated T-cell functions could play a role in the prevention of T-H/T(C)1-related autoimmune diseases but also predispose toward T-H/T(C)2-mediated allergic reactions.