Background The pathogenesis of systemic lupus erythematosus (SLE) is characterized by dysregulated dendritic cells (DCs) with over-production of type I interferon and hyperactive adaptive immune response. Clinical benefits of tolerogenic DCs have recently been shown in some murine models of immune mediated diseases.
Objectives To examine if alternatively activated DCs (aaDCs) derived from SLE patients possess tolerogenic properties and to delineate the underlying mechanisms.
Methods Lupus and healthy control aaDCs were generated by treating monocyte derived DCs using combination of 1α,25-Dihydroxyvitamin D3 (vitD3) and dexamethasone followed by maturation by lipopolysaccharide (LPS). These aaDCs were examined for phenotype and tolerogenic functions compared with LPS-matured DCs (matDCs). Activation markers and intracellular cytokine expression of T cells and/or DCs were measured by flow cytometry. ELISA was used to measure cytokine levels in supernatant. Western blot was performed for detection of RelB protein expression.
Results Compared with matDCs, lupus aaDCs displayed semi-mature phenotype with low level of expression of co-stimulatory molecules and maturation markers (CD83, CD40), that remained stable despite challenge by CD40L, CpG-DNA and SLE serum. These aaDCs also possessed tolerogenic phenotype with suppressive effect on allogeneic T cell activation (CD25 and CD69 expression) and proliferation comparable to normal aaDCs. Lupus and normal aaDCs were shown to polarize normal and lupus naïve CD45RA+ T cells into T effector cells that were characterized by production of high level of IL-10, expression of Foxp3 mRNA and antigen-nonspecific suppressive effect on allogeneic third-party T cells. On the other hand, lupus and normal aaDCs skewed memory CD45RO+ T cells to less inflammatory phenotype with reduced expression of IFN-γ and IL-17. Although aaDCs displayed a cytokine profile of IL-12loIL-10hi, addition of neutralizing anti-IL-12 and exogenous IL-10 to culture conditions did not reverse the suppressive effect of aaDCs on activation and proliferation of allogeneic T cells, suggesting their tolerogenicity cannot be accounted by cytokine imbalance between IL-12 and IL-10. On the other hand, aaDCs were found to express reduced level of RelB, a transcription factor regulating DC differentiation and maturation.
Conclusions Lupus aaDCs demonstrated tolerogenic properties with induction of IL-10 producing T cells that have regulatory functions. Reduced expression of RelB in aaDCs may be the underlying mechanism for their tolerogenicity.
Disclosure of Interest None Declared
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