Manipulating Ig production in vivo through CD180 stimulation
Chaplin, Jay Wesley
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CD180 is homologous to TLR4 and regulates TLR4 signaling, yet its function is unclear. This thesis reports that injection of anti-CD180 mAb into mice induced rapid polyclonal IgG, with up to 50-fold increases even in immunodeficient mice. Anti-CD180 rapidly increased transitional B cell number in contrast to anti-CD40 which induced primarily FO B cell and myeloid expansion. Combinations of anti-CD180 with MyD88-dependent TLR ligands biased B cell fate toward synergistic proliferation. Thus, CD180 stimulation induces B cell proliferation and differentiation, causing rapid increases in IgG, and integrates MyD88-dependent TLR signals to regulate proliferation and differentiation. This thesis also reports that targeting Ag to CD180 rapidly induces Ag-specific IgG. IgG responses were robust, diverse, and partially T cell-independent, as both CD40- and T cell deficient mice responded after CD180 targeting. IgG production occurred with either hapten- or OVA-conjugated anti-CD180, and was specific for Ag coupled to anti-CD180. Simultaneous BCR and CD180 stimulation enhanced activation compared to either stimulus alone. Adoptive transfer experiments demonstrated that CD180 expression was required on B cells but not on DCs for Ab induction. Surprisingly, Ag-targeting was also efficient in BAFF-R KO mice despite their lack of mature B cells. Ag-anti-CD180 induced rapid and robust expansion of Ag-specific B cells with a germinal center phenotype and differentiation to plasma cells. Mice preimmunized with Ag-anti-CD180 displayed Ag-specific IgG forming cells when boosted, demonstrating that Ag-anti-CD180 induces immunologic memory. A weak but significant memory response was evident even in CD40 KO mice. Targeting Ag to CD180 may provide a benefit in therapeutic vaccination or for the immunocompromised.