VITAMIN-D DIFFERENTIALLY REGULATES B7.1 AND B7.2 EXPRESSION ON HUMAN PERIPHERAL-BLOOD MONOCYTES

The hormonal active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25 (OH)(2)D-3), inhibits (through an unknown mechanism) the ability of mo nocytes/macrophages to induce T-cell activation. For T cells to be opt imally activated, recognition of antigen/major histocompatibility comp lexes (MHC) by the T-cell receptor (TCR) must be accompanied by a seco nd costimulatory signal. Considerable experimental data now suggest th at this costimulatory signal is predominantly generated by B7.1 and/or B7.2 molecules, expressed on antigen-presenting cells (APC), when eng aged to their counter-receptor, CD28, present on T cells. To determine whether the inhibitory effect of 1,25(OH)(2)D-3 on monocytes/macropha ges might involve modulation of the expression of B7.1 and B7.2 molecu les, we analysed (by flow cytometry) the influence of 1,25(OH)(2)D-3 a nd an analogue, KH 1060, on the expression of these two molecules at t he surface of resting human peripheral blood monocytes. In parallel, w e tested the effect of these two agents on human monocyte expression o f cell-surface markers (CD14 and CD4) and antigen-presenting molecules (MHC class I and MHC class II). Our results showed that both 1,25(OH) (2)D-3 and KH 1060 inhibited the basal expression of B7.2 in a dose- a nd time-dependent manner, without affecting B7.1. Moreover, these two compounds increased CD14 and reduced MHC class II and CD4 expression. Furthermore, the effect of 1,25(OH)(2)D-3 on B7 molecule expression in combination with lipopolysaccharide (LPS) or cytokines, including int erleukin-10 (IL-IO), interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), was studied. The 1,25(OH)(2)D-3-induced B7.2 down-regulation was still detectable when monocytes were activated by IL-IO, IFN-gamma and TNF-alpha but not with LPS. Moreover, the induct ion of B7.1 by TNF-alpha was inhibited by addition of 1,25(OH)(2)D-3. We conclude that the ability of 1,25(OH)(2)D-3 to decrease B7.2 expres sion on human monocytes might contribute to its inhibitory effect on A PC-dependent T-cell activation and to its immunosuppressive properties observed in autoimmune diseases and organ transplantation.