Human T Cells Express a Functional Ionotropic Glutamate Receptor GluR3, and Glutamate by Itself Triggers Integrin-Mediated Adhesion to Laminin and Fibronectin and Chemotactic Migration

Abstract

T cells may encounter glutamate, the major excitatory neurotransmitter in the nervous system, when patrolling the brain and in glutamate-rich peripheral organs. Moreover, glutamate levels increase in the CNS in many pathological conditions in which T cells exert either beneficial or detrimental effects. We discovered that normal human T cells, human T leukemia cells, and mouse anti-myelin basic protein T cells express high levels of glutamate ion channel receptor (ionotropic) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype 3 (GluR3). The evidence for GluR3 on T cells includes GluR3-specific RT-PCR, Western blot, immunocytochemical staining and flow cytometry. Sequencing showed that the T cell-expressed GluR3 is identical with the brain GluR3. Glutamate (10 nM), in the absence of any additional molecule, triggered T cell function: integrin-mediated T cell adhesion to laminin and fibronectin, a function normally performed by activated T cells only. The effect of glutamate was mimicked by AMPA receptor-agonists and blocked specifically by the selective receptor-antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo[f]quinoxalin-2,3-dione (NBQX), and by relevant anti-integrin mAbs. Glutamate also increased the CXCR4-mediated T cell chemotactic migration toward the key chemokine CXCL12/stromal cell-derived factor-1. GluR3 expression on normal, cancer and autoimmune-associated T cells and the ability of glutamate to directly activate T cell function could be of substantial scientific and clinical importance to normal neuroimmune dialogues and to CNS diseases and injury, and especially to: 1) T cell transmigration to the CNS and patrolling in the brain, 2) T cell-mediated multiple sclerosis, and 3) autoimmune epilepsy, as neurotoxic anti-GluR3 Abs are found and suspected to cause/potentiate seizures and neuropathology in several types of human epilepsies. Thus far, GluR3 was found only on neurons and glia cells; our results reveal a novel peripheral source of this antigenic receptor.

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

“…Bar, 10 m. C, ultrastructural characterization of human isolated islets exposed to elevated glutamate concentration. an inverted ␤-cell/␣-cell ratio and glucagon hypersecretion (30,42,43) and also during "insulitis" in T1DM islets because dendritic and T cells can release glutamate (44,45). Of note, changes in glutamate concentration in the islet have been reported in response to high glucose (46), and increased glutamate levels have been found in sera of subjects with both T1DM (47) and T2DM (48).…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Moderately higher physiological concentrations (micromolar range) of glutamate promote T-cell proliferation via inotropic receptors (AMPA and NMDA) and decreased apoptosis via mGluRs. High concentrations (millimolar range) in a variety of pathological conditions can activate mGluR5 to decrease T-cell proliferation and mGluR1 to increase inflammatory (eg, IFN-γ) cytokine release (Ganor et al, 2003). T-cell dysfunction is one of the least explored areas in neuropsychiatry and represents a gap in our current knowledge regarding cellular regulation of glutamate neurotransmission (Ellwardt et al, 2016;Walsh et al, 2014b).…”

“…Resting T cells also express NMDA receptors and exhibit a dose-dependent functional response to glutamate exposure (Levite, 2014). Low physiological concentrations (in nanomolar range) of glutamate appear to increase T-cell adhesion and facilitate chemotactic migration (Ganor et al, 2003). Moderately higher physiological concentrations (micromolar range) of glutamate promote T-cell proliferation via inotropic receptors (AMPA and NMDA) and decreased apoptosis via mGluRs.…”

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

“…Glutamate has been recently shown to have a role not only as a neurotransmitter, but also as an immunomodulator [50,51]. In 2003, AMPA-activated ionotropicGluRs were detected in human lymphocytes [52]. Moreover, glutamate was shown to be able to activate and modulate T cell activity by itself [50,[53][54][55].…”