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Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
The majority of resting normal human T cells, like neuronal cells, express functional receptors for glutamate (the major excitatory neurotransmitter in the CNS) of the ionotropic 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor subtype 3 (GluR3). Glutamate by itself (
10 nM) activates key T cell functions, including adhesion to fibronectin and laminin and chemotactic migration toward CXCL12/stromal cell-derived factor 1. In this study, we found by GluR3-specific immunostaining, flow cytometry, and Western blots that GluR3 cell surface expression decreases dramatically following TCR activation of human T cells. CXCR4, VLA-4, and VLA-6 also decrease substantially, whereas CD147 increases as expected, after TCR activation. Media of TCR-activated cells "eliminates" intact GluR3 (but not CXCR4 and VLA-6) from the cell surface of resting T cells, suggesting GluR3 cleavage by a soluble factor. We found that this factor is granzyme B (GB), a serine protease released by TCR-activated cells, because the extent of GluR3 elimination correlated with the active GB levels, and because three highly specific GB inhibitors blocked GluR3 down-regulation. Media of TCR-activated cells, presumably containing cleaved GluR3B peptide (GluR3 aa 372–388), inhibited the specific binding of anti-GluR3B mAb to synthetic GluR3B peptide. In parallel to losing intact GluR3, TCR-activated cells lost glutamate-induced adhesion to laminin. Taken together, our study shows that "classical immunological" TCR activation, via autocrine/paracrine GB, down-regulates substantially the expression of specific neurotransmitter receptors. Accordingly, glutamate T cell neuroimmune interactions are influenced by the T cell activation state, and glutamate, via AMPA-GluR3, may activate only resting, but not TCR-activated, T cells. Finally, the cleavage and release to the extracellular milieu of the GluR3B peptide may in principle increase its antigenicity, and thus the production, of anti-self GluR3B autoantibodies, which activate and kill neurons, found in patients with various types of epilepsy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Mia Levite, Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail address: mia.levite{at}weizmann.ac.il
2 Abbreviations used in this paper: GluR, glutamate receptor; NMDA, N-methyl-D-aspartate; AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GluR3, ionotropic AMPA-receptor subtype 3; MBP, myelin basic protein; CSF, cerebrospinal fluid; ECF, extracellular fluid; GB, granzyme B; SDF-1, stromal cell-derived factor 1.
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  D. Pleasure Diagnostic and Pathogenic Significance of Glutamate Receptor Autoantibodies Arch Neurol, May 1, 2008; 65(5): 589 - 592. [Abstract] [Full Text] [PDF]
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 C. Poulopoulou Comment on "TCR Activation Eliminates Glutamate Receptor GluR3 from the Cell Surface of Normal Human T Cells, via an Autocrine/Paracrine Granzyme B-Mediated Proteolytic Cleavage" J. Immunol., February 15, 2008; 180(4): 2007 - 2007. [Full Text] [PDF]
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M. Levite Response to Comment on "TCR Activation Eliminates Glutamate Receptor GluR3 from the Cell Surface of Normal Human T Cells, via an Autocrine/Paracrine Granzyme B-Mediated Proteolytic Cleavage" J. Immunol., February 15, 2008; 180(4): 2007 - 2007. [Full Text] [PDF]
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