Towards a unifying model for B-cell receptor triggering

Antibodies are exceptionally versatile molecules with remarkable flexibility in their binding properties. Their natural targets range from small-molecule toxins, across viruses of different sizes, to bacteria and large multicellular parasites. The molecular determinants bound by antibodies include proteins, peptides, carbohydrates, nucleic acids, lipids and even synthetic molecules that have never existed in nature. Membrane-anchored antibodies also serve as receptors on the surface of the B cells that produce them. Despite recent structural insights, there is still no unifying molecular mechanism to explain how antibody targets (antigens) trigger the activation of these B-cell receptors (BCRs). After cognate antigen encounter, somatic hypermutation and class-switch recombination allow BCR affinity maturation and immunoglobulin class-specific responses, respectively. This raises the fundamental question of how one receptor activation mechanism can accommodate a plethora of variant receptors and ligands, and how it can ensure that individual B cells remain responsive to antigen after somatic hypermutation and class switching. There is still no definite answer. Here we give a brief historical account of the different models proposed to explain BCR triggering and discuss their merit in the context of the current knowledge of the structure of BCRs, their dynamic membrane distribution, and recent biochemical and cell biological insights. The mechanisms by which antigen triggers B-cell activation are incompletely understood. In this Review, Degn and Tolar discuss the different models of B-cell receptor triggering that have been proposed over the years in the light of recent insights.