Synaptic Interactions in Germinal Centers

Ilenia Papa, Carola G. Vinuesa

The germinal center (GC) is a complex, highly dynamic microanatomical niche that allows the generation of high-affinity antibody-producing plasma cells and memory B cells. These cells constitute the basis of long-lived highly protective antibody responses. For affinity maturation to occur, B cells undergo multiple rounds of proliferation and mutation of the genes that encode the immunoglobulin V region followed by selection by specialized T cells called follicular helper T (TFH) cells. In order to achieve this result, the GC requires spatially and temporally coordinated interactions between the different cell types, including B and T lymphocytes and follicular dendritic cells. Cognate interactions between TFH and GC B cells resemble cellular connections and synaptic communication within the nervous system, which allow signals to be transduced rapidly and effectively across the synaptic cleft. Such immunological synapses are particularly critical in the GC where the speed of T-B cell interactions is faster and their duration shorter than at other sites. In addition, the antigen-based specificity of cognate interactions in GCs is critical for affinity-based selection in which B cells compete for T cell help so that rapid modulation of the signaling threshold determines the outcome of the interaction. In the context of GCs, which contain large numbers of cells in a highly compacted structure, focused delivery of signals across the interacting cells becomes particularly important. Promiscuous or bystander delivery of positive selection signals could potentially lead to the appearance of long-lived self-reactive B cell clones. Cytokines, cytotoxic granules, and more recently neurotransmitters have been shown to be transferred from TFH to B cells upon cognate interactions. This review describes the current knowledge on immunological synapses occurring during GC responses including the type of granules, their content, and function in TFH-mediated help to B cells.