Fcγ receptors as regulators of immune responses

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Abstract
The family of Fc receptors for IgG (FcγRs) is broadly expressed by cells of haematopoietic origin and consists of one inhibitory and several activating receptors that differ in their affinity and specificity for immunoglobulin subclasses. On innate immune effector cells, activating and inhibitory FcγRs set a threshold for cell activation by immune complexes. Important examples for effector responses that are regulated by FcγRs are phagocytosis, ADCC and the release of inflammatory mediators. On dendritic cells (DCs), paired FcγR expression regulates cell maturation and antigen presentation, thereby indirectly controlling the cellular immune response. On B cells, the inhibitory FcγRIIB is essential for the maintenance of humoral tolerance. It acts as a late checkpoint at the level of class-switched memory B cells, plasmablasts or plasma cells. In addition, FcγRIIB has an important role in regulating plasma-cell homeostasis and survival. The antibody–FcγR interaction is influenced by several factors that have an impact on the expression level of activating and inhibitory FcγRs (such as cytokines) or change the affinity of the antibody–FcγR interaction (such as differential antibody glycosylation). Depending on the specific glycosylation pattern, IgG molecules can have enhanced pro- or anti-inflammatory activities. Importantly, antibody glycosylation is regulated during immune responses. Targeting the factors that influence the antibody–FcγR interaction might open new avenues for immunotherapeutic interventions in autoimmune and malignant diseases.