The potential of central nervous system (CNS)-derived cells for initiating T cell responses is not known. Using the capacity of unprimed T cells to respond to allogeneic determinants on antigen presenting cells (APC). we assessed the ability of microglial cells lo act as stimulators of primary T cell responses in vitro. For this purpose, microglial cells were activated with lipopolysaccharide (LPS). interferon-gamma (IFN-γ), or by phagocytosis of progenitor oligodendrocytes and subsequently tested for their ability to induce a proliferative response of naive, resting T cells. Activated microglial cells induced a significant proliferation of virgin, alloreactive CD4⁺ and CD8⁺ T lymphocytes, with a more substantial response of highly purified CD4⁺ than of CD8⁺ expressing T cells. Phagocytosis activation was the most efficient stimulus to induce this APC competence on microglial cells. By contrast. IFN-γ pretreated. MHC-expressing astrocytes were unable to induce similar responses of alloreactive CD4⁺ or CD8⁺ T cells under the same experimental conditions. Collectively, our data suggest the role of activated microglia as the fully immunocompetent accessory cell population of the CNS.