T Cells Inhibit Hippocampal Regeneration in Mice Following Trimethyltin-Induced Neurodegeneration

Although the regenerative capacity of the mammalian brain is quite weak, internal neural stem/progenitor cells (NSPCs) in the brain can provide new neurons into the brain lesions. Leukocytes, particularly T cells, infiltrate injured brain tissue and participate in immune reactions and have a large impact on the progress of the lesion. However, the effect of T cells on the regeneration of brain tissue remains unclear. Trimethyltin (TMT) is an organotin that has selective neurotoxicity on granule neurons in the hippocampal dentate gyrus. TMT-induced hippocampal lesion is mostly regenerated because adjacent NSPCs can provide new granule neurons. In this study, using TMT-injected mice as a model of brain tissue regeneration, the influence of T cells on hippocampal tissue regeneration was investigated. When TMT was injected into nude mice lacking T cells, they exhibited shortened immobility time in the tail suspension test, indicating improved functional outcomes. Immunohistochemical analysis revealed improved granule neuron replenishment and enhanced survival and differentiation of new neurons in nude mice. Microglial reaction characterized by phagocytosis and astrocytic reaction with brain-derived neurotrophic factor (BDNF) expression were enhanced in nude mice. Hippocampal tissue regeneration was impaired when nude mice were repopulated with total lymphocytes or with CD4- or CD8-positive cells. Repopulations of T cells altered microglial reactions; however, changes in astrocytes were not reproduced. These results suggest that both helper and cytotoxic T cells inhibit hippocampal tissue regeneration by preventing neuronal replenishment. T cells also affect lesion clearance by microglia and astrocytic BDNF expression; however, their effect is stronger on microglia. These findings provide novel insights into the immune regulation of brain tissue regeneration.