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

Abstract

IntroductionProtection against different classes of pathogens requires the activation of Ag-presenting dendritic cells (DCs) to express factors that promote the development of distinct effector Th-cell subsets, which are specialized to combat the class of pathogen involved. 1 Effective T cell-mediated immunity against extracellular bacteria requires DCs to produce IL-1␤, IL-6, and IL-23 that contribute to the development of Th17 cells. 2,3 The pathogen-induced production of cytokines by DCs is induced on sensing of pathogens by pattern-recognition receptors (PRRs), including TLRs, C-type lectins, Nod-like receptors, and RIG-I-like receptors. [4][5][6][7] Although triggering of individual PRRs is known to induce cytokine production, it is becoming increasingly clear that the ultimate amount and the profile of cytokine production by DCs crucially depends on cross-talk between multiple PRRs. 8-10 However, our knowledge on these cross-talk mechanisms is likely to be still largely incomplete. 10 In this respect, the role of Fc␥Rs, the family of high-and low-affinity receptors for IgG, in the induction of cytokine production did not receive much attention. IgG is the most prevalent immunoglobulin in the blood and body tissues. 11,12 Because of the high levels of IgG directed against numerous polyreactive bacterial Ags, invading bacteria are efficiently opsonized as soon as they penetrate the body's barriers, even during primary infection. [13][14][15][16][17] IgG opsonization can directly lead to pathogen inactivation via complement activation, but can also result in a variety of responses by different effector immune cells such as cell degranulation, production of reactive oxygen species (ROS), or Ab-dependent cellular cytotoxicity (ADCC). 18,19 In addition, binding of opsonized pathogens to low-affinity Fc␥Rs on DCs mediates phagocytosis, degradation and subsequent presentation of pathogen-derived Ags to T cells. 20 Fc␥R stimulation also induces DC maturation. [21][22][23] However, the triggering of Fc␥Rs on DCs results in no or only low production of cytokines and has not been demonstrated to play a major role in polarization of human T-cell responses in healthy donors. 21,22 In the present study, we have taken into account that in most conditions DCs will engage bacteria that are IgG opsonized and that such DCs will be simultaneous triggered via Fc␥Rs and bacterial sensors. We here report that the engagement of DCs with opsonized bacteria resulted in strongly up-regulated production of selected cytokines, including IL-1␤ and IL-23, which favored the development of Th17 cells. This effect was fully dependent on stimulation of the low-affinity IgG receptor Fc␥RIIa (also known as CD32a), which synergized with TLRs for the amplification of Th17-promoting cytokines by both enhancing cytokine transcription and by activating caspase-1. Taken together, these data identified cross-talk between TLRs and Fc␥RIIa as a novel mechanism by which DCs promote the development of protective effector T cells in response to bacteria. ...

Antibody-Opsonized Bacteria Evoke an Inflammatory Dendritic Cell Phenotype and Polyfunctional Th Cells by Cross-Talk between TLRs and FcRs

“…Thus, both MyD88-dependent TLR signaling and FcRdependent ITAM signaling are required for functional cross-talk. Furthermore, cross-talk was not confined to FcgRII on DCs, as previously suggested (41). Both FcgRI and FcaRI were able to synergize with TLR4 on DCs and neutrophils.…”

Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated protein antibodies

“…Synergy between TLR and Fc receptor triggering has been previously described for basophils and dendritic cells,32 39 and likely represents a physiological function of the immune system to mount an enhanced response when antibodies are produced after the first encounter with a pathogen.…”

Effects of C-reactive protein on the neutrophil respiratory burstin vitro

“…77,78 This study has focused on the effects of low levels of soluble, pentameric CRP on the neutrophil respiratory burst. However, altered or modified CRP (mCRP) has been detected in a variety of tissues.…”