Increased expression of herpesvirus entry mediator in 1,25-dihydroxyvitamin D3-treated mouse bone marrow-derived dendritic cells promotes the generation of CD4+CD25+Foxp3+ regulatory T cells

Abstract

Dendritic cells (DCs) can initiate immune responses or induce immune tolerance. 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is a secosteroid hormone that can induce tolerogenic dendritic cells favoring the induction of regulatory T cells (Treg). The present study revealed a tolerogenic effect of 1,25(OH)2D3 on the phenotype and function of ovalbumin (OVA)-activated mouse bone marrow-derived DCs. Three inhibitory molecules associated with tolerogenic DCs, programmed death-ligand-1 (PD-L1), PD-L2 and herpesvirus entry mediator (HVEM) and the expression of co-stimulatory molecules (CD80, CD86 and CD40) on 1,25(OH)2D3-treated DCs were examined. The levels of interleukin (IL)-2, IL-6 and IL-10 secreted by 1,25(OH) 2D3-treated DCs were analyzed. The capability of 1,25(OH) 2D3-treated DCs to induce CD4+CD25+Foxp3 + Treg and the stimulation of allogeneic CD4+ T-cell proliferation in mixed lymphocyte reaction (MLR) was studied. 1,25(OH) 2D3-treated DCs induced up to 21.0-fold upregulation of the HVEM expression and 4.1-fold enhancement of the HVEM expression upon activation with OVA [OVA-D3/immature (im)DCs]. PD-L1 was not affected by 1,25(OH) 2D3-treated DCs and downregulated PD-L2 expression on 1,25(OH) 2D3-treated DCs and OVA-D3/imDC. The expression of co-stimulatory molecules (CD80, CD86 and CD40) was downregulated in 1,25(OH) 2D3-treated DCs and OVA-D3/imDC. Furthermore, 1,25(OH) 2D3-treated DCs secreted much higher levels of IL-10, however lower levels of IL-2 and IL-6 compared with the activated control DCs. Together with this pattern of cytokines, 1,25(OH)2D3-treated DCs exhibited low allogeneic CD4+ T-cell stimulatory activity and a higher number of CD4+CD25+Foxp3+ cells in the MLR cultures but not in the activated control DCs. These findings indicate that 1,25(OH) 2D3 possesses the immunosuppressive properties by upregulating the expression of the inhibitory molecules, HVEM, which may be therapeutically useful in controlling chronic immune and/or inflammatory diseases.