Important role for FcγRIIB on B lymphocytes for mucosal antigen-induced tolerance and Foxp3⁺regulatory T cells

FcγRIIB, the only FcgR expressed on B cells, is important in the maintenance of immunological tolerance to self-Ags. In this study, we investigated the role of FcγRIIB in Ag-specific CD4 T cell tolerance induced by mucosally administered Ag (OVA) coupled to cholera toxin B subunit (Ag/CTB) or given alone. We found that sublingual administration of Ag/CTB conjugate or intragastric administration of a >100-fold higher dose of Ag alone efficiently suppressed parenteral immunization-induced Ag-specific T cell proliferation and delayed-type hypersensitivity responses in FcγRIIB-expressing wild-type (WT), but not FcγRIIB-/-, mice. Such mucosally induced tolerance (oral tolerance) associated with induction of Ag-specific Foxp3+regulatory T cells was restored in FcγRIIB-/-mice by adoptive transfer of either WT B cells or WT dendritic cells before the mucosal Ag/ CTB treatment; it was even more pronounced in μMT mice that received FcγRIIB-overexpressing B cells before treatment. Furthermore, cell transfer in either WT or μMT mice of WT but not FcγRIIB-/-B cells pretreated for 1 h in vitro with Ag/CTB conjugate induced Ag-specific immunological tolerance, which was further enhanced by adoptive transfer of WT B cells pretreated with anti-Ag IgG immune complexed Ag/CTB. We conclude that FcγRIIB expression on B cells, in addition to dendritic cells, is important for mucosal induction of Ag-specific immune tolerance.