title: Neuroprotective immunity: T cell-derived glutamate endows astrocytes with a neuroprotective phenotype.
abstract: 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 beta-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.
authors.affiliation: Redox Biology Center, University of Nebraska, Lincoln, NE 68588, USA.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Garg
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kipnis
mesh_terms: D000693:Anaerobiosis / Q000276:immunology; D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology* / Q000633:toxicity; D007111:Immunity, Cellular; D016130:Immunophenotyping; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D018384:Oxidative Stress / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D013438:Sulfhydryl Compounds; D019344:Lactic Acid; D018698:Glutamic Acid