Investigation of neural-like signalling in human germinal centres

Abstract

Protective high affinity antibody responses depend on competitive selection of B cells carrying somatically-mutated BCRs by Tfh cells in germinal centres (GC). The rapid T:B synaptic interactions that occur during this process are reminiscent of those within the nervous system. Therefore, we asked whether neural transmission pathways participate in GC selection. This thesis shows that a proportion of human, but not mouse, GC Tfh cells contained dense-core granules marked by chromogranin B, which are normally found in neuronal pre-synaptic terminals and their main function is to store neuropeptides and/or catecholamines, such as dopamine. Further, GC Tfh cells contained high concentrations of dopamine and released it upon cognate interaction with GC B cells. In a search for dopamine-mediated effects on human GC B cells, we identified selective and rapid upregulation of ICOSL. ICOSL-mediated costimulation has been shown to increase the contact area between GC B cells and Tfh cells, which maximises antigen presentation and delivery of Tfh cell help. In mice, upregulation of ICOSL by GC B cells is driven by TFH expressed CD40L in a process that takes hours. In this thesis, we show that ICOSL upregulation by human GC B cells did not depend on CD40L. of note, high amount of intracellular preformed ICOSL was expressed in human GC B cells and translocated to the surface within minutes of stimulation by dopamine. ICOSL was able to enhance accumulation of CD40L and chromogranin B granules at the human Tfh:GC B cell synapse and increase the contact area. Further, mathematical modelling suggests that faster dopamineinduced T:B interactions do not change affinity maturation but rather increase total output and accelerate it by days. This thesis demonstrates that Tfh cells have co-opted yet another form of synaptic help that may provide an advantage in the face of infection.