Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4⁺Foxp3⁺ regulatory T cells by 1,25-dihydroxyvitamin D₃

1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) is a secosteroid hormone that renders dendritic cells (DCs) tolerogenic, favoring the induction of regulatory T cells. Induction of DCs with tolerogenic properties by 1,25(OH)₂D₃ is associated with increased selective expression of immunoglobulin-like transcript 3 (ILT3), suggesting its involvement in the immunoregulatory properties of this hormone. Here we show an in vivo correlate of the increased ILT3 expression on DCs in healing psoriatic lesions following topical treatment with the 1,25(OH)₂D₃ analog calcipotriol. Analysis of DC subsets reveals a differential regulation of ILT3 expression by 1,25(OH)₂D₃, with a marked upregulation in myeloid DCs but no effect on its expression by plasmacytoid DCs. A regulatory role for ILT3 expressed on DCs is indicated by the increased interferon-γ (IFN-γ) secretion promoted by anti-ILT3 addition to cultures of DCs and T cells, but this effect is blunted in 1,25(OH) ₂D₃-treated DCs, suggesting ILT3-independent mechanisms able to regulate T-cell activation. Although ILT3 expression by DCs is required for induction of regulatory T cells, DC pretreatment with 1,25(OH) ₂D₃ leads to induction of CD4⁺Foxp3⁺ cells with suppressive activity irrespective of the presence of neutralizing anti-ILT3 monoclonal antibody (mAb), indicating that ILT3 expression is dispensable for the capacity of 1,25(OH)₂D₃-treated DCs to induce regulatory T cells.