Cells that are capable of initiating immune reactions in the central nervous system (CNS) seem to be microglia, since they are the predominant CNS cell type expressing major histocompatibility complex (MHC) class II molecules. However, the capacity of microglia to induce myelin antigen-specific T lymphocyte activation is not yet well defined. With a coculture system allowing phagocytosis by microglia of progenitor or mature oligodendrocytes (synthesizing myelin basic protein, MBP), we show the ability of phagocytosis-activated microglia to express MHC class II antigen and to strongly induce T cell proliferation. The T cell proliferation was either mitogen mediated or antigen specific (MBP). Activation of microglia by phagocytosis may represent a major step in initializing immune responses in the CNS.