| Plasmacytoid dendritic cell precursors (pDCs), also known as type 1 interferon-producing cells(IPCs) are extraordinary at producing IFN-α upon exposure to virus or bacterial CpG, which play a central role in the pathogenesis of systemic lupus erythematosus (SLE).pDCs display plasma cell morphology as smooth, round and 8-10 μm in diameter. It represent 0.2%-0.8% of human peripheral blood mononuclear cells and selectively express Toll-like receptor (TLR) 7 and TLR9, which are known as the ligand of DNA virus and CpG oligodeoxynucleotides (CpG ODNs), (TLR9 ligand) or single-stranded viral RNA (TLR7 ligand).Type 1 IFN can promote the function of NK cells, B cells, T cells and regulate the function of monocytes and myeloid dendritic cell (mDC) during an antiviral immune response. At a later stage of viral infection, pDCs differentiate into a unique type of mature dendritic cell, which directly regulates the function of T cell and thus links innate and adaptive immune responses. It is thought that pDCs are involved in the pathogenesis of some diseases such as infectious diseases, cancer, and autoimmune diseases. Better understanding pDCs biology will help to design the new approaches to the treatment of such diseases.BDCA2 is a plasmacytoid dendritic cell-specific antigen. BDCA-2 is a novel type II C-type lectin of 213 amino acids (aa), which close to the gene encoding the dendritic cell immunoreceptor (DCIR).Anti - BDCA2 monoclonal antibodies are rapidly internalized and efficiently presented to T cells, indicating that BDCA-2 could play a role in ligand intern-alization and presentation. Furthermore, ligation of BDCA-2 potentlysuppresses induction of type 1 interferon production in pDCs, presumably by a mechanism dependent on calcium mobilization and protein-tyrosine phosphorylation by src-family protein-tyrosine kinases. The production of type 1 interferon by pDCs is considered to be a major pathophysi-ological factor in systemic lupus erythematosus (SLE), triggering of BDCA-2 should be evaluated as therapeutic strategy for blocking production of interferon in SLE.To further investigate the role of BDCA2 in the negative regulation of pDCs, we used CpG ODN as a activator of pDCs and observed the biological changes of CpG ODN induced pDCs when ligated with anti-BDCA2 mAb AC144. At first, we investigated the expression of BDCA2 at different development stage of pDCs. We found that BDCA2 was downregulated to a low but detectable level on pDCs during development. CpG, but not CD40-ligation, enabled pDCs to lose the expression of BDCA2, suggesting that BDCA2 is still present on pDCs for a long time when pDCs differentiated to activated or mature dendritic cells.Then we investigated the biological function of BDCA2 during immune response of pDCs. Pre-ligation of BDCA2 on pDCs significantly inhibited CpG-mediated enhanced expression of CD40 and CD86 as well as production of IFN-α and IL-6, but had no effects on HLA-DR expression by pDCs. Furthermore, ligation of BDCA2 with anti-BDCA2 mAb AC144 suppressed CpG-activated pDC-mediated the proliferation, activation and production of IFN-γ and IL-10 of CD4~+ T cells. The phenotype analysis of these CD4+ T cells, we found a CD4+CD25+ regulatory T cells were inhibited. Interestingly, when we collected 13 PBMC samples of SLE patients and 8 of normal donors, and detected the percentage of BDCA2+ cells in PBMCs and its expression levels on pDCs. We found that expression levels of BDCA2 on pDCs in SLE patients were much lower than that on pDCs of healthy donors and the percentage of BDCA2+ pDCs in PBMCs also significantly decreased.In conclusion, BDCA2 can inhibit the activation of pDCs, and further inhibit the proliferation, activation of CD4+ T cell by CpG ODN-activated pDCs indicating that BDCA2 can function as a negative regulator in immune response induced by pDCs. The negative regulation of pDCs by BDCA2 signaling and its relationship with SLE will help us to better understanding the regulatory function of pDCs, and thus give us some clues to develop therapeatic approaches for SL... |
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