Synergy between anti-commensal antibodies and IL-10 in gut homeostasis and disease

To limit immune responses to gut-resident microbes, mucus and the epithelial barrier physically separate the host immune system from microbial communities. Immunoglobulin A (IgA) antibodies are known to help to regulate the colonization and functions of mucus-associated commensals. However, the mechanisms whereby other isotypes, including IgG, interface with other components of the immune system to promote tolerance of MA microbes are still being unraveled. Our lab previously showed that, in mice with impaired production of T-dependent (TD) anti- commensal antibodies, IgA- and IgG-mediated recognition of mucus-derived bacterial antigens is significantly reduced. Moreover, transient depletion of IL-10-producing cells from mice devoid of TD antibodies resulted in rapid onset colitis. Therefore, we hypothesized that anti-commensal antibodies synergize with IL-10 to promote immune homeostasis in the colon. Here, we show that, relative to wild type mice, there are increased levels of colonic IL-10-producing CD4 T cells in mice lacking both IgG and IgA (Aicda^-/-) but not in mice lacking only IgA (Iga^-/-). Additionally, transient depletion of IL-10-producing cells resulted in severe colitis in Aicda^-/- but not Iga^-/- mice. Importantly, this colitis developed despite elevated levels of IgM in the colon mucus layer of Aicda^-/- mice. Furthermore, we observed elevated levels of IgG in the colon mucus layer of Iga^-/- mice suggesting a potentially compensatory role for IgG in mice devoid of IgA. Collectively, our data suggest an important contribution for anti- commensal IgG, including in combination with IL-10, in promoting immune tolerance of border-dwelling microbes.