OLIGODENDROCYTE LYSIS BY CD4(+) T-CELLS INDEPENDENT OF TUMOR-NECROSIS-FACTOR

The capacity of human CD4(+) T cells to lyse heterologous human oligodendrocytes in an 18-hour chromium 51-release assay was compared to that of systemic blood-derived macrophages and central nervous system-derived microglia. CD4(+) T cells, activated with either phytohemagglutinin, anti-CD3 antibody, or antigen (myelin basic protein), could induce lysis of the oligodendrocytes whereas macrophages and microglia, activated with interferon-gamma and lipopolysaccharide, could not. The CD4(+) T-cell effect was not inhibited with an anti-tumor necrosis factor-alpha-neutralizing antibody. Both the CD4(+) T cells and the macrophages could induce lysis of tumor necrosis factor-sensitive rodent cell lines, Wehi 164, and L929; these effects were inhibited with anti-tumor necrosis factor antibody. Pretreatment of the CD4(+) T cells with cyclosporine or mitomycin C did not inhibit oligodendrocyte lysis. These results indicate that at least in vitro, CD4(+) T cells can induce a form of oligodendrocyte injury that is not reproduced by macrophages or microglia or by tumor necrosis factor. The non-major histocompatibility complex (MHC)-restricted injury of oligodendrocytes induced by both myelin antigen-reactive and mitogen-stimulated T cells may provide a basis whereby cytotoxic CD4(+) T cells could interact with a target cell that does not express MHC class II molecules. Our results suggest that immune-mediated oligodendrocyte/myelin injury, as is postulated to occur in the disease multiple sclerosis, may involve multiple effector mechanisms.