Follicular exclusion of autoreactive B cells requires FcγRIIb

In non-autoimmune mice, the 3H9 transgenic Ig heavy chain can pair with endogenous Igλ1 light chains to generate B cells with specificity for DNA. These autoreactive cells are actively regulated in vivo, as indicated by the exclusion of λ1 cells from the splenic B cell follicle and the absence of auto-antibody production. To study the role of Fcγ receptor IIb (FcγRIIb) in peripheral B cell tolerance, FcγRIIb^-/- mice were crossed with C57BL/6 mice bearing a site-directed knock-in of the 3H9 transgene. 3H9FcγRIIb^-/- mice become autoreactive, lose the follicular exclusion of anti-DNA B cells and instead have λ1 B cells located within splenic germinal centers. They have increased frequencies of splenic auto-antibody-producing cells and elevated titers of IgG anti-DNA auto-antibody. The data implicate an FcγRIIb-dependent checkpoint that can exclude autoreactive B cells from splenic follicles. By restricting their participation in germinal center reactions, this putative checkpoint helps attenuate the production of potentially pathogenic auto-antibodies. The data further suggest that this FcγRIIb-dependent regulation is B cell autonomous.