1,25-dihydroxyvitamin D3 inhibits IFN-γ and IL-4 levels during in vitro polarization of primary murine CD4+ T cells

Following their activation, naive CD4(+) T cells can differentiate into one of two effector cell subsets, Th1 and Th2. These two subsets have different cytokine secretion patterns and thus mediate separate arms of the immune response. It has been established that the fat-soluble vitamin D-3 metabolite 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) and its nuclear receptor, the vitamin D receptor, play an important role in the immune system primarily through the transcriptional inhibition of cytokine genes that either are required for Th1 differentiation or are products of differentiated Th1 cells. Therefore, we wanted to test directly the ability of 1,25(OH)(2)D-3 to alter the Th differentiation process. Our results indicate that 1,25(OH)(2)D-3 inhibits not only the Th1 cytokine IFN-gamma but also the Th2 cytokine IL-4 in naive CD62 ligand(+)CD4(+) T cells during their in vitro polarization. This effect is most dramatic when the ligand is present from the onset of the differentiation process. If the ligand is added after the polarization has ensued, the inhibition is significantly diminished. In activated (CD62 ligand(-)CD4(+)) T cells, 1,25(OH)(2)D-3 is still able to inhibit IFN-gamma but has no effect on IL-4 production. Our results also indicate that inhibition of these two cytokines in naive cells by vitamin D receptor and its ligand is neither a result of a cell cycle block nor an inhibition of Th1 or Th2 transcription factor expression but, rather, at least in the case of Th2 differentiation, an attenuation of IL-4 transcription by the receptor.