Sustained calcium signalling and caspase-3 activation involve NMDA receptor in thymocytes in contact with dendritic cells

L-glutamate, the major excitatory neurotransmitter, also plays a role in non-neuronal tissues and modulates immune responses. Whether NMDA receptor (NMDAR) signalling is involved in T cell development is unknown. Here we show that mouse thymocytes expressed an array of glutamate receptors, including NMDARs subunits. Sustained calcium signals, and caspase-3 activation in thymocytes were induced by interaction with antigen-pulsed DCs and were inhibited by NMDAR antagonists MK801 and memantine. NMDAR was transiently activated, triggered the sustained calcium signal, and was corecruited with the PDZ-domain adaptor PSD-95 to thymocyte-DC contact zones. While T cell receptor (TCR) activation was sufficient for relocalization of NMDAR and PSD-95 at the contact zone, NMDAR could be activated only in a synaptic context. In these T-DC contacts, thymocyte activation occurred in the absence of exogenous glutamate, indicating that DCs could be a physiological source of glutamate. DCs expressed glutamate, glutamate-specific vesicular VGLUT transporters and were capable of fast glutamate release through a Ca-dependent mechanism. We propose that glutamate released by DCs could elicit focal responses through NMDAR-signalling in T cells undergoing apoptosis. Thus, synapses between T and DCs could provide a functional platform for coupling TCR activation and NMDAR signalling which might reflect on T cell development and modulation of the immune response.