FcγRIIB Regulates Nasal and Oral Tolerance: A Role for Dendritic Cells

Abstract

Mucosal tolerance prevents the body from eliciting productive immune responses against harmless Ags that enter the body via the mucosae, and is mediated by the induction of regulatory T cells that differentiate in the mucosa-draining lymph nodes (LN) under defined conditions of Ag presentation. In this study, we show that mice deficient in FcγRIIB failed to develop mucosal tolerance to OVA, and demonstrate in vitro and in vivo a critical role for this receptor in modulating the Ag-presenting capacity of dendritic cells (DC). In vitro it was shown that absence of FcγRIIB under tolerogenic conditions led to increased IgG-induced release of inflammatory cytokines such as MCP-1, TNF-α, and IL-6 by bone marrow-derived DC, and increased their expression of costimulatory molecules, resulting in an altered immunogenic T cell response associated with increased IL-2 and IFN-γ secretion. In vivo we could show enhanced LN-DC activation and increased numbers of Ag-specific IFN-γ-producing T cells when FcγRIIB−/− mice were treated with OVA via the nasal mucosa, inferring that DC modulation by FcγRIIB directed the phenotype of the T cell response. Adoptive transfer of CD4+ T cells from the spleen of FcγRIIB−/− mice to naive acceptor mice demonstrated that OVA-responding T cells failed to differentiate into regulatory T cells, explaining the lack of tolerance in these mice. Our findings demonstrate that signaling via FcγRIIB on DC, initiated by local IgG in the mucosa-draining LN, down-regulates DC activation induced by nasally applied Ag, resulting in those defined conditions of Ag presentation that lead to Tr induction and tolerance.

Important Role for FcγRIIB on B Lymphocytes for Mucosal Antigen-Induced Tolerance and Foxp3+ Regulatory T Cells

“…We confirmed a previous study (30) Purified B cells, pulse-treated with OVA/CTB in vitro and extensively washed before adoptive transfer to either WT or mMT mice, also conferred tolerance in WT mice, as well as in mMT mice, provided that the transferred Ag/CTB-treated B cells expressed FcgRIIB. mMT mice, apart from their lack of B cells, contain functional FcgRIIB-expressing DCs and other types of APCs (34) and yet they have a defective oral tolerance response unless adoptively receiving FcgRIIB-expressing B cells (21).…”

“…Samsom et al (30) showed that the absence of FcgRIIB can convert tolerogenic T cell responses into immunogenic responses associated with increased IL-2 and IFN-g secretion, and they suggested that the disappearance of tolerance resulted from the production of proinflammatory cytokines, such as MCP-1, TNF-a, and IL-6, together with increased expression of costimulatory molecules by DCs lacking the inhibitory FcgRIIB (30). Such a process, although mediated not only by DCs but also, and perhaps even more importantly, via FcgRIIB 2/2 B cells, is also suggested by our findings that mMT mice that adoptively received inhibitory signaling on non-B cell APCs, such as DCs, and increasing their propensity for stimulating Teff, rather than Treg, responses.…”

“…Given the important role of the expression of FcgRIIB on B cells for mucosal induction of Ag-specific T cell tolerance, as well as the report by Samsom et al (30) suggesting a similar role for FcgRIIB-expressing DCs, we tested, in a similar way as reported for B cells (Fig. 4), the ability of DCs isolated from WT or FcgRIIB 2/2 mice after the standard three-dose s.l.…”

“…FcgRIIB deficiency is associated with increased inflammation, allergy, and development of chronic autoimmunity (26,29,30). Moreover, these knockout mice were described to display impaired mucosal tolerance after nasal administration of Ag (OVA), resulting in reduced suppression of eosinophilia and IgE production in murine allergic rhinitis and delayed-type hypersensitivity (DTH) reactions, which was assumed to reflect the lack of FcgRIIB expression on DCs (30,31). The role of FcgRIIB expressed on B cells in oral tolerance has not been examined.…”

Regulation of allergy by Fc receptors

“…These mice displayed impaired nasal and oral tolerance, suggesting that FcγRIIB are involved in tolerance to air-borne and food allergens. FcγRIIB expressed on dendritic cells were indeed shown to regulate antigen presentation, cytokine secretion and the generation of regulatory T cells in this model of nasal tolerance [43].…”