The Inhibitory FcγIIb Receptor Dampens TLR4-Mediated Immune Responses and Is Selectively Up-regulated on Dendritic Cells from Rheumatoid Arthritis Patients with Quiescent Disease

Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for Fc gamma Rs and TLRs is accepted, their precise involvement remains to be elucidated. F gamma RIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory Fc gamma RIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory Fc gamma RIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating Fc gamma Rs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcYRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking Fc gamma RIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory Fc gamma RIIb in the induction of these phenomena. This TLR4-Fc gamma RIIb interaction was shown to dependent on the PI3K and Akt pathway. The Journal of Immunology, 2009, 183: 4509-4520.