A balance of inhibitory and activating signals determines the function of dendritic cells (DCs) in the immune response, which may be regulatory or stimulatory. Defects of inhibitory receptor FccRIIb are involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE), in which high levels of circulating immune complexes (IC) exist. Our previous study showed that IC/Ig can suppress TLR4-triggered inflammatory responses in macrophages via FccRIIb. This led us to question whether IC/Ig can polarize FccRIIb-overexpressing DCs (DC-FccRIIb) to be tolerogenic, thus attenuating lupus progression once infused in vivo. First, we found that IC/Ig markedly inhibited LPS-or CpG-induced DC maturation, enhanced tolerogenicity of DCs via FccRIIb, and induced massive prostaglandin E2 (PGE2) secretion from DCs, both contributing to T-cell hyporesponsiveness. Endogenous Ig and lupus-derived IC also exhibited the same effect. DC-FccRIIb, transfected with recombinant adenovirus encoding FccRIIb, displayed enhanced tolerogenic function and produced more PGE2 in the presence of IC, thus further inhibiting T-cell responses. Importantly, in vivo infusion with DC-FccRIIb significantly reduced kidney damage and prolonged the survival of lupus-prone MRL/lpr mice either before or after the onset of clinic lupus. Therefore, administration of DC-FccRIIb may be a new approach to attenuate lupus progression.Keywords: DCs . FccRIIb . IC . Immunotherapy . SLE Supporting Information available online
IntroductionAs a highly heterogeneous population, DCs not only play an important role in initiating and enhancing immune response but also contribute to the maintenance of tolerance via various mechanisms, including direct inhibition of T-cell response, induction of T-cell anergy or Treg and directing Th subset polarization [1][2][3][4][5][6][7]. Immature DCs or tolerogenic DC subsets induce hyporesponsiveness of T cells to self-antigens through mechanisms including expression of low level of costimulatory molecules, expression of inhibitory molecules such as PD-L, secretion of immunosuppressive factors such as IL-10, TGF-b, prostaglandin E2 (PGE2), IDO,. Clearly, several approaches may be taken to enhance DC tolerogenecity. We previously demonstrated that genetic modification of immature DCs with inhibitory cytokines such as IL-10, TGF-b or soluble TNF Ã These authors contributed equally to the work.
1154receptor could inhibit pathogenesis of autoimmune diseases or prolong allograft survival [14][15][16]. In addition, exosomes derived from IL-10-treated or IL-4 gene-modified DCs could also suppress inflammation and attenuate progression of autoimmune diseases [17,18]. In spite of the existing findings, new approaches to enhance DC tolerogenecity or utilizing new subsets of tolerogenic/suppressive/regulatory DCs for the control of inflammation and autoimmune diseases with increased efficacy and identifying the underlying mechanisms remains a hot topic in immunology.Ligation of Fc receptors for IgG (FcgRs) by immune comple...