Immune regulation by human dendritic cells

Abstract

Human dendritic cell (DC) subsets are composed of CD141⁺ myeloid DCs (mDCs), CD1c⁺ mDCs, and plasmacytoid DCs (pDCs). These DC subsets have different functions, and reagents that differentially regulate functions of the subsets may represent novel therapies for immune disorders. A proteasome inhibitor for multiple myeloma, bortezomib, suppresses the survival and immunostimulatory function of pDCs by targeting two critical points, intracellular trafficking of nucleic acid-sensing Toll-like receptors and endoplasmic reticulum homeostasis. A tyrosine kinase inhibitor for chronic myeloid leukemia with multiple targets, dasatinib, suppresses IFN-α production by pDCs stimulated with CpG DNA without reducing viability. This suppression is likely due to the abrogation of endosomal retention of CpG DNA, which is critical for the large amount of IFN-α production by pDCs. It has been reported that pDCs cause inflammatory disorders such as lupus and psoriasis. Thus, these studies illustrate that vesicular trafficking characteristic of pDCs may constitute a target to develop novel therapies for inflammatory disorders. 1α, 25-dihydroxyvitamin D₃ (VD₃) is an important immunomodulatory vitamin. VD₃ induces CD1c⁺ mDCs to produce a vitamin A derivative, retinoic acid (RA). Furthermore, the CD1c⁺ mDCs induce naïve CD4⁺ T cells to differentiate into guthoming Th2 cells in an RA-dependent manner. The “vitamin D – CD1c⁺ mDC – RA” axis may constitute an important immune component for maintaining tissue homeostasis in humans. Long-lasting efforts to clarify the mechanisms by which DCs perform immunoregulatory functions and to apply the accumulating knowledge to developing novel therapies will continue to be an exciting field in immunology.