This study analyzes how the antigen specificity, the subtype, and the activation state of T cells modulate their recently discovered neuroprotective potential. We assessed the prevention from neuronal damage in organotypic entorhinal–hippocampal slice cultures after co-culture with Th1 and Th2 cells either specific for myelin basic protein (MBP) or ovalbumin (OVA). We found that MBP-specific Th2 cells were the most effective in preventing central nervous system (CNS) tissue from secondary injury. This neuroprotective T cell effect appears to be mediated by soluble factors. After stimulation with phorbol myristate acetate and ionomycin, all T cells were most effective in preventing neuronal death. Our data show that the T cell subtype and activation state are important features in determining the neuroprotective potential of these cells.