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

The capacity of human CD4(+) T cells to lyse heterologous human oligod endrocytes in an 18-hour chromium 51-release assay was compared to tha t of systemic blood-derived macrophages and central nervous system-der ived microglia. CD4(+) T cells, activated with either phytohemagglutin in, anti-CD3 antibody, or antigen (myelin basic protein), could induce lysis of the oligodendrocytes whereas macrophages and microglia, acti vated 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 macropha ges could induce lysis of tumor necrosis factor-sensitive rodent cell lines, Wehi 164, and L929; these effects were inhibited with anti-tumo r necrosis factor antibody. Pretreatment of the CD4(+) T cells with cy closporine 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 o r microglia or by tumor necrosis factor. The non-major histocompatibil ity complex (MHC)-restricted injury of oligodendrocytes induced by bot h myelin antigen-reactive and mitogen-stimulated T cells may provide a basis whereby cytotoxic CD4(+) T cells could interact with a target c ell that does not express MHC class II molecules. Our results suggest that immune-mediated oligodendrocyte/myelin injury, as is postulated t o occur in the disease multiple sclerosis, may involve multiple effect or mechanisms.