Intracellular Antibody Immunity and the Cytosolic Fc Receptor TRIM21

Until recently, it was thought that antibody effector mechanisms were mediated purely by Fc receptors expressed on professional cells, following capture of immune complexes in the extracellular space. Recently a new Fc receptor, TRIM21, was discovered that is expressed by cells of all histogenetic lineages and which mediates immune responses intracellularly. This new receptor possesses many unique structural and functional properties. TRIM21 binds both IgG and IgM, interacts primarily with the CH3 rather than CH2 domain and engages two heavy chains simultaneously. This latter property allows TRIM21 to bind antibodies with a higher affinity than any other Fc receptor. TRIM21 is cytosolic, has both effector and signalling functions and is exquisitely conserved in mammals. The discovery of this missing part of humoral immunity has important implications for where and how antibodies work.