FcγRIIb balances efficient pathogen clearance and the cytokine-mediated consequences of sepsis

The immune response to infection must be controlled to ensure it is optimal for defense while avoiding the consequences of excessive inflammation, which include fatal septic shock. Mice deficient in FcgammakIIb, an inhibitory immunoglobulin G Fc receptor, have enhanced immune responses. Therefore, we examined whether FcgammaRIIb controls the response to Streptococcus pneumoniae. Macrophages from FcgammaRIlb-deficient mice showed increased antibody-dependent phagocytosis of pneumococci in vitro, and consistent with this infected FcgammaIIb-deficient mice demonstrated increased bacterial clearance and survival. In contrast, previously immunized FcgammaKIIb-deficient mice challenged with large inocula showed reduced survival. This correlated with increased production of the sepsis-associated cytokines tumor necrosis factor a and interleukin 6. We propose that FcgammaRIIb controls the balance between efficient pathogen clearance and the cytokine-mediated consequences of sepsis, with potential therapeutic implications.