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

• Published in: Cell death and differentiation Vol. 18; no. 1; pp. 99 - 108
• Main Authors: Affaticati, P, Mignen, O, Jambou, F, Potier, M-C, Klingel-Schmitt, I, Degrouard, J, Peineau, S, Gouadon, E, Collingridge, G L, Liblau, R, Capiod, T, Cohen-Kaminsky, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2011; Nature Publishing Group
• Subjects: 631/250/1619/554; 631/250/1933; 631/80/86/1999; Amino Acid Transport System X-AG - metabolism; Animals; Antigens; Apoptosis; Biochemistry; Biomedical and Life Sciences; Calcium - metabolism; Calcium Signaling; Caspase 3 - metabolism; Cell Biology; Cell cycle; Cell Cycle Analysis; Cell death; Cytokines; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disks Large Homolog 4 Protein; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Glutamic Acid - metabolism; Glutamic Acid - pharmacology; Guanylate Kinases; Immunology; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Lymphocytes; Memantine - pharmacology; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Mice; Nervous system; Original Paper; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Stem Cells; Thyroid Gland - cytology; Thyroid Gland - immunology; Thyroid Gland - metabolism; France; immunological synapse; NMDAR; calcium signalling; glutamate signalling; thymocyte
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.79

L-glutamate, the major excitatory neurotransmitter, also has a role in non-neuronal tissues and modulates immune responses. Whether NMDA receptor (NMDAR) signalling is involved in T-cell development is unknown. In this study, we show that mouse thymocytes expressed an array of glutamate receptors, including NMDARs subunits. Sustained calcium (Ca
2+
) signals and caspase-3 activation in thymocytes were induced by interaction with antigen-pulsed dendritic cells (DCs) and were inhibited by NMDAR antagonists MK801 and memantine. NMDARs were transiently activated, triggered the sustained Ca
2+
signal and were corecruited with the PDZ-domain adaptor postsynaptic density (PSD)-95 to thymocyte-DC contact zones. Although 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 glutamate transporters and were capable of fast glutamate release through a Ca
2+
-dependent mechanism. We suggest 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.