Vulnerability of human neurons to T cell-mediated cytotoxicity.
Axonal and neuronal loss occurs in inflammatory diseases of the CNS such as multiple sclerosis. The cause of the loss remains unclear. We report that polyclonally activated T cells align along axons and soma of cultured human neurons leading to substantial neuronal death. This occurs in an allogeneic and syngeneic manner in the absence of added Ag, requires T cells to be activated, and is mediated through cell contact-dependent mechanisms involving FasL, LFA-1, and CD40 but not MHC class I. Activated CD4(+) and CD8(+) T cell subsets are equally neuronal cytotoxic. In contrast to neurons, other CNS cell types (oligodendrocytes and astrocytes) are not killed by T cells. These results demonstrate for the first time the high and selective vulnerability of human neurons to T cells, and suggest that when enough activated T cells accumulate in the CNS, neuronal cytotoxicity can result through Ag-independent non-MHC class I mechanisms.
Giuliani
Fabrizio
F
Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
Goodyer
Cynthia G
CG
Antel
Jack P
JP
Yong
V Wee
VW
D019138:Antibodies, Blocking / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002450:Cell Communication / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D053222:Fas Ligand Protein; D005333:Fetus; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D009474:Neurons / Q000166:cytology* / Q000276:immunology*; D009836:Oligodendroglia / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
D019138:Antibodies, Blocking; D019013:CD40 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007106:Immune Sera; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D019014:fas Receptor