title: 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 alpha-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.
authors.affiliation: Weizmann Institute of Science, Rehovot, Israel. Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Ganor
authors.forename: Michal
authors.initials: M
authors.lastname: Besser
authors.forename: Naomie
authors.initials: N
authors.lastname: Ben-Zakay
authors.forename: Tamar
authors.initials: T
authors.lastname: Unger
authors.forename: Mia
authors.initials: M
authors.lastname: Levite
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001483:Base Sequence; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D007608:Kainic Acid / Q000494:pharmacology; D007797:Laminin / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D005353:Fibronectins; D007074:Immunoglobulin G; D016023:Integrins; D007797:Laminin; D012333:RNA, Messenger; D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid