Axonal damage induced by invading T cells in organotypic central nervous system tissue in vitro: involvement of microglial cells.
Neuroinflammation in the course of multiple sclerosis and experimental autoimmune encephalomyelitis results in demyelination and, recently demonstrated, axonal loss. Invading neuroantigen specific T cells are the crucial cellular elements in these processes. Here we demonstrate that invasion of activated T cells induces a massive microglial attack on myelinated axons in entorhinal-hippocampal slice cultures. Flow cytometry analysis of activation markers revealed that the activation state of invading MBP-specific T cells was significantly lower in comparison to PMA-activated T cells. Moreover, MBP-specific T cells showed a significantly lower secretion of IFN-gamma. Conversely, MBP-specific T cells displayed a significantly higher potential to trigger activation of microglial cells, i.e. upregulation of MHC class II and ICAM-1 expression, and, most importantly, microglial phagocytosis of pre-traced axons. Our data suggest that this was mediated via specific cellular interactions of T cells and microglial cells since IFN-gamma alone was not sufficient to induce axonal damage while such damage was apparent in response to TNF-alpha which is released by activated microglial cells. TNF-alpha secretion by both T cell populations was negligible. Thus, MBP-specific T cells which invade nervous tissue in the course of neuroinflammation are more effective in axon-damaging recruiting microglial cells than activated T cells of other specificities.
Gimsa
U
U
Department of Cell and Neurobiology, Institute of Anatomy, Humboldt-University Clinic Charité, Berlin, Germany. ulrike.gimsa@charite.de
Peter
S V
SV
Lehmann
K
K
Bechmann
I
I
Nitsch
R
R
D000818:Animals; D001369:Axons / Q000473:pathology*; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D018728:Entorhinal Cortex / Q000473:pathology*; D006624:Hippocampus / Q000473:pathology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D009924:Organ Culture Techniques; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma