Antibody-mediated oligodendrocyte cell death requires an astrocyte-derived cosignal

We have described a monoclonal antibody (mAb), 2B10, that identifies a cell-surface protein expressed only on oligodendrocytes, the myelin-forming cells in the vertebrate central nervous system. To examine the effect of mAb 2B10 on oligodendrocyte development and survival, purified antibody was added to dissociated cultures of neonatal rat spinal cord. Addition of mAb 2B10 induced significant cell death, with a reduction of approximately 70% in the number of differentiated oligodendrocytes. The number of astrocytes was unaltered. Addition of mAb 2B10 did not affect the proliferation or differentiation of oligodendrocyte precursors. MAb 2B10-induced death of differentiated oligodendrocytes was independent of complement but did require an environmental signal. In purified oligodendrocyte cultures, binding of the antibody to oligodendrocytes did not induce cell death. Conditioned medium and transwell coculture experiments indicated that the required environmental signals were not soluble. By contrast, when oligodendrocytes were cocultured with astrocytes, addition of mAb 2B10 specifically induced cell death of differentiated oligodendrocytes, suggesting that a locally acting cosignal from astrocytes was required to facilitate the cell death. This cosignal was provided by live astrocytes but not by fixed astrocytes, microglia, or fibroblasts. Such antibody-induced oligodendrocyte cell death may explain in part the loss of myelin-forming cells in demyelination conditions, such as multiple sclerosis.