Fcγ receptor IIb (FcγRIIb) is an essential negative regulator of B cells that blocks B cell receptor (BCR) signaling and triggers c‐Abl–dependent apoptosis of B cells. FcγRIIb‐deficient mice display splenomegaly with expansion of B cells, leading to lupus. FcγRIIb‐I232T is a hypofunctional polymorphism associated with lupus susceptibility in humans, an autoimmune disease linked to diminished deletion of autoreactive B cells. In the context of the FcγRIIb‐I232T polymorphism, we investigated the role of FcγRIIb in the deletion of low‐affinity germinal center (GC) B cells, an important mechanism for preventing autoimmunity.

We generated FcγRIIb^232T/T mice to mimic human FcγRIIb‐I232T carriers and immunized mice with chicken gamma globulin (CGG)–conjugated NP, a T cell–dependent antigen, to examine the response of GC B cells.

Compared to wild‐type (WT) mice, FcγRIIb^232T/T mice showed increased numbers of low‐affinity NP‐specific IgG and NP‐specific B cells and plasma cells; additionally, the expression of a somatic mutation (W33L) in their V_H186.2 genes encoding high‐affinity BCR was reduced. Notably, FcγRIIb^232T/T mice had a higher number of GC light zone B cells and showed less apoptosis than WT mice, despite having equivalent follicular helper T cell numbers and function. Moreover, phosphorylation of c‐Abl was reduced in FcγRIIb^232T/T mice, and treatment of WT mice with the c‐Abl inhibitor nilotinib during the peak of GC response resulted in reduced affinity maturation reminiscent of FcγRIIb^232T/T mice.

Our findings provide evidence of a critical role of FcγRIIb/c‐Abl in the negative selection of GC B cells in FcγRIIb^232T/T mice. Importantly, our findings indicate potential benefits of up‐regulating FcγRIIb expression in B cells for treatment of systemic lupus erythematosus.