Microglia arise from CD45 ؉ bone marrow precursors that colonize the fetal brain and play a key role in central nervous system inflammatory conditions. We report that parenchymal microglia are uncommitted myeloid progenitors of immature dendritic cells and macrophages by several criteria, including surface expression of ''empty'' class II MHC protein and their cysteine protease (cathepsin) profile. Microglia express receptors for stem cell factor and can be skewed toward more dendritic cell or macrophage-like profiles in response to the lineage growth factors granulocyte͞ macrophage colony-stimulating factor or macrophage colonystimulating factor. Thus, in contrast to other organs, where terminally differentiated populations of resident dendritic cells and͞ or macrophages outnumber colonizing precursors, the majority of microglia within the brain remain in an undifferentiated state. P arenchymal microglia are ubiquitously distributed in the central nervous system (CNS) where they comprise up to 20% of the total non-neuronal cell population (1). These cells are thought to play a prominent role in infectious, traumatic, inflammatory, ischemic, and degenerative CNS disease processes. The role of microglia as mediators of CNS inflammation is, in part, promulgated through their ability to process and present class II-restricted antigens to CD4 ϩ T cells (2, 3).Microglial cells are derived from CD45 ϩ bone marrow precursors of the myeloid lineage, which also can give rise to macrophages, dendritic cells (DC), and granulocytes. Studies by using irradiation chimeras show that the adult brain has two subsets of microglia (3): the resting microglia, which are ramified throughout the brain parenchyma and are mostly a permanent population, and the perivascular microglia, which are periodically replaced by bone marrow-derived elements and are strategically located in the basal lamina of brain capillaries and the choroid plexus. The only known difference between these microglial populations is CD45 expression, which is high on perivascular and low on parenchymal microglia (4). In general, CD45 high cells also express more class II MHC and costimulatory molecules. However, it is still unclear whether the parenchymal and perivascular microglia represent the same cellular population at a different activation state, owing to microenvironmental influences, or whether these populations are more distinct.Traditionally, parenchymal microglia have been considered to be resident macrophages of the brain. However, several pieces of evidence suggest a more complex picture. For example, op͞op mice, which are deficient in macrophage colony-stimulating factor (M-CSF) and consequently are depleted of tissue-resident macrophages in several areas, do not exhibit a large reduction in the overall brain microglial population (5-7). Also, previous studies show generation of ''DC-like'' antigen-presenting cells (APC) from mixed glial cultures (8). Cells clearly displaying macrophage-and DC-like characteristics have been identified from the CNS of m...