IgG opsonization of bacteria promotes Th17 responses via synergy between TLRs and Fc gamma RIIa in human dendritic cells

Dendritic cells (DCs) are essential in inducing adaptive immune responses against bacteria by expressing cytokines that skew T-cell responses toward protective Th17 cells. Although it is widely recognized that induction of these cytokines by DCs involves activation of multiple receptors, it is still incompletely characterized which combination of receptors specifically skews Th17-cell responses. Here we have identified a novel role for Fc gamma RIIa in promoting human Th17 cells. Activation of DCs by bacteria opsonized by serum IgG strongly promoted Th17 responses, which was Fc gamma RIIa-dependent and coincided with enhanced production of selected cytokines by DCs, including Th17-promoting IL-1 beta and IL-23. Notably, Fc gamma RIIa stimulation on DCs did not induce cytokine production when stimulated individually, but selectively amplified cytokine responses through synergy with TLR2, 4, or 5. Importantly, this synergy is mediated at 2 different levels. First, TLR-Fc gamma RIIa costimulation strongly increased transcription of pro-IL-1 beta and IL-23p19. Second, Fc gamma RIIa triggering induced activation of caspase-1, which cleaves pro-IL-1 beta into its bioactive form and thereby enhanced IL-1 beta secretion. Taken together, these data identified cross-talk between TLRs and Fc gamma RIIa as a novel mechanism by which DCs promote protective effector Th17-cell responses against bacteria. (Blood. 2012;120(1):112-121)