Serotonin is generally thought of as a neurotransmitter that is passed between neurons at neuronal synapses for the regulation of appetite, mood and pain. Now, Peta O'Connell and colleagues report that serotonin might be delivered from dendritic cells (DCs) to T cells across the immunological synapse in a manner similar to that which occurs between neurons. They propose that this is a new form of rapid communication between DCs and T cells and that this might have important implications for the regulation of T-cell responses.

A role for serotonin in the immune response has previously been reported: serotonin has been shown to be a mediator that is released by mast cells and platelets in response to injury or pro-inflammatory signals. In this study, the authors show that, although DCs cannot themselves synthesize serotonin, they express the serotonin transporter SERT (also known as SLC6A4). Cell-surface expression of SERT by DCs was increased following activation and maturation, and this enabled the cells to take up serotonin from their microenvironment. Presumably, mature DCs could acquire serotonin from platelets or mast cells at inflammatory sites, but the authors show that activated T cells can synthesize serotonin for uptake by mature DCs.

Serotonin taken up by activated DCs was stored in vesicular compartments and not degraded by the serotonin catabolic enzymes monoamine oxidase A (MAOA) and MAOB, owing to downregulation of expression of these enzymes after DC activation. By loading DCs with radiolabelled serotonin, the authors next showed that stored serotonin is rapidly released, through exocytosis, in the presence of extracellular ATP, which induces the mobilization of intracellular calcium as occurs in DCs on interaction with T cells.

The authors then asked what effect serotonin might have on T cells. Treatment of T cells with exogenous serotonin reduced the concentration of the intracellular-signalling molecule cyclic AMP (cAMP), which inhibits T-cell proliferation at high concentrations, indicating that serotonin might terminate the initial increase in cAMP concentration that occurs after T-cell-receptor ligation and therefore promote T-cell activation.

Given these data, the authors suggest that DCs shuttle serotonin, possibly synthesized by activated T cells, to the synaptic space between a DC and a naive T cell. This allows localized delivery of a high concentration of this labile molecule, which is required for activating the naive T cell.