Adoptive transfer of T lymphocytes in immunodeficient mice influences epileptogenesis and neurodegeneration in a model of temporal lobe epilepsy

作者：Deprez Francine; Zattoni Michela; Mura Maria Luisa; Frei Karl; Fritschy Jean Marc^*

来源：Neurobiology of Disease, 2011, 44(2): 174-184.

DOI：10.1016/j.nbd.2011.06.011

• Kainic acid
• Spontaneous recurrent seizures
• Hippocampus
• Neurodegeneration
• EEG

Intra-hippocampal injection of kainic acid (KA) in adult mice causes a focal lesion in the CA1 area and hilus of the dentate gyrus, as well as pronounced granule cell hypertrophy and dispersion. The lesion results in chronic focal seizures, with a two-week delay following KA-induced status epilepticus. Furthermore, seizures are preceded by infiltration of T lymphocytes into the lesioned tissue and of macrophage-like cells, strongly immunopositive for the monocyte marker F4/80, into the dentate gyros, where they regulate granule cell dispersion and survival. Unexpectedly, depletion of CD4(+) and/or CD8(+) T lymphocytes by targeted gene deletion results in a marked shortening of the delay prior to seizure onset, suggesting a role of adaptive immunity in epileptogenesis (Zattoni et al. 2011, J. Neurosci, 31, 4037). Here, we investigated the specific role of adaptive immunity in this TLE model by adoptive i.v, transfer of immunopurified T cells in mutant mice lacking either CD4(+) T cells (MHCII-knockout), CD8(+) T cells (beta 2-microglobulin-knockout), or both populations (RAG1-knockout mice). EEG analysis in mutants mice injected with KA two days after the T cell transfer revealed that grafting of the missing T cell population had no influence on seizure onset, but strongly influenced F4/80(+) macrophage-like cell infiltration in the dentate gyros. Specifically, CD8(+) T cells in beta 2-microgloblin-knockout mice enhanced macrophage recruitment, whereas CD4(+) T cells transferred in MHCII-knockout and in RAG1-knockout mice blocked macrophage infiltration, leading to reduced granule cell dispersion and survival, thereby worsening the KA-induced lesion. These results suggest that intact adaptive immunity is required for delayed seizure onset in this mouse model of TLE and unravel complex interactions between T cells and mononuclear phagocytes for the control of neuronal integrity and survival in the lesioned brain.

• 出版日期2011-11