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RIIB Regulates Nasal and Oral Tolerance: A Role for Dendritic Cells
* Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Faculteit der Geneeskunde, MB Amsterdam, The Netherlands;
Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; and
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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 Fc
RIIB 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 FcRIIB under tolerogenic conditions led to increased IgG-induced release of inflammatory cytokines such as MCP-1, TNF-
, 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- secretion. In vivo we could show enhanced LN-DC activation and increased numbers of Ag-specific IFN--producing T cells when FcRIIB–/– mice were treated with OVA via the nasal mucosa, inferring that DC modulation by FcRIIB directed the phenotype of the T cell response. Adoptive transfer of CD4+ T cells from the spleen of FcRIIB–/– 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 FcRIIB 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.
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