The role of astrocytes and microglia as antigen-presenting cells in the brain is still controversial. In this study we have analyzed and compared aspects of the molecular machinery that underlies MHC class II trafficking in immunocompetent astrocytes and microglia. We show that IFN-+ -stimulated microglia possess active cathepsin L and cathepsin S, and efficiently degrade the invariant chain, unlike IFN-+ -stimulated astrocytes that express cathepsin L but not cathepsin S. The lack of cathepsin S proves to be dramatic for the antigen-presentation capacity of astrocytes, which is nearly abolished when these cells are stimulated by a combination of IFN-+ and TNF- § . TNF- § indeed decreases cathepsin L activity as we show here, leading to alterations in invariant chain processing, and hence in MHC class II trafficking in astrocytes. Cystatin C inhibits cathepsin L activity in astrocytes, but does not regulate cathepsin L and cathepsin S activity in microglia. We therefore identify cathepsin L and cathepsin S as key components in the regulation of the immune potential of astrocytes and microglia, and provide evidence for a cell-specific regulation exerted by IFN-+ and TNF- § on the expression and activity of cathepsins.