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* Redox Biology Center and
Department of Biochemistry, University of Nebraska, Lincoln, NE 68588; and
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198
A well-controlled T cell response to CNS injury may result in increased neuronal survival. However, the precise mechanism of T cell-induced neuroprotection is unknown. In this study, we report the unexpected finding that during culture of T cells, high levels of glutamate accumulate, which are efficiently cleared if T cells are cocultured with astrocytes. The T cell-derived glutamate elicits in turn, the release of neuroprotective thiols (cysteine, glutathione, and cysteinyl-glycine) and lactate from astrocytes. Media obtained from astrocytes conditioned in the presence of T cells reduce neuronal apoptosis induced by oxidative stress in primary neuronal cultures from 48 ± 14 to 9 ± 4% (p < 0.001). Inhibition of glutamate-dependent signaling during astrocyte-T cell cocultivation by a glutamate uptake inhibitor, L-aspartic acid β-hydroxamate, abolishes this neuroprotective effect. The ability of astrocytes to clear extracellular glutamate is impaired under conditions of oxidative stress. We demonstrate that T cells, via secreted cytokines, restore glutamate clearance capacity of astrocytes under oxidative conditions. Furthermore, under normoxic conditions, glutamate-buffering capacity of astrocytes is increased upon cocultivation with T cells. It is known that, following CNS injury, astrocytes can respond with beneficial or destructive effects on neurons. However, the context and signaling mechanisms for this dual astrocytic response are unknown. Our results implicate T cells as potential determinants of the context that elicits a protective role for astrocytes in the damaged CNS.
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1 Current address: Department of Biological Chemistry, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0606.
2 Address correspondence and reprint requests to the following authors at their current addresses: Dr. Ruma Banerjee, Department of Biological Chemistry, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0606. E-mail address: rbanerje{at}umich.edu or Dr. Jonathan Kipnis, Department of Neuroscience, University of Virginia, 409 Lane Road, Charlottesville, VA 22908. E-mail address: kipnis{at}virginia.edu
3 Abbreviations used in this paper: AβH, L-aspartic acid β-hydroxamate; MS, mass spectrometry; t-BuOOH, tert-butyl hydroperoxide.
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