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

Fc gamma RIIB, the only Fc gamma R expressed on B cells, is important in the maintenance of immunological tolerance to self-Ags. In this study, we investigated the role of Fc gamma RIIB 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 Fc gamma RIIB-expressing wild-type (WT), but not Fc gamma RIIB-/-, mice. Such mucosally induced tolerance (oral tolerance) associated with induction of Ag-specific Foxp3(+) regulatory T cells was restored in Fc gamma RIIB-/- 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 mu MT mice that received Fc gamma RIIB-overexpressing B cells before treatment. Furthermore, cell transfer in either WT or mu MT mice of WT but not Fc gamma RIIB-/- 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 Fc gamma RIIB expression on B cells, in addition to dendritic cells, is important for mucosal induction of Ag-specific immune tolerance.