Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Allele-dependent expression of activating FcγRIIc on human B cells enhances humoral immunity. B Cell Balancing Act Immune cells walk a tight rope as defenders of the body: If there’s too little activation, an infection will go unchecked, whereas if there’s too much, the immune cell may attack the body’s own cells. Hence, these cells are highly regulated through negative and positive signals. For B cells, some of these signals come through Fc receptors, which bind the Fc tail of antibodies. Now, Li et al. report the activating receptor FcγRIIc on B cells. B cells had been thought to express only inhibitory Fcγ receptor, FcγRIIb, which serves as feedback inhibition for immunoglobulin G production. The authors report that human B cells may also express FcγRIIc, which counterbalances negative signaling through FcγRIIb. FcγRIIc enhanced humoral immune responses to vaccination both in transgenic mice and in humans in an anthrax vaccine trial. What’s more, the FCGR2C-ORF allele is associated with autoimmunity risk in humans. By determining which individuals express this allele, these data will help guide more precise antibody-based therapy. B cells are pivotal regulators of acquired immune responses, and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can substantially alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides immunoglobulin G (IgG)–mediated negative modulation through a tyrosine-based inhibition motif, which down-regulates B cell receptor–initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. We report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax vaccination in a human anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of unidirectional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell–targeted antibody-based therapy.