Immunocompetent astrocytes and microglia display major differences in the processing of the invariant chain and in the expression of active cathepsinL and cathepsin S

The role of astrocytes and microglia as antigen-presenting cells in the bra in is still controversial, in this study we have analyzed and compared aspe cts of the molecular machinery that underlies MHC class II trafficking in i mmunocompetent astrocytes and microglia. We show that IFN-gamma -stimulated microglia possess active cathepsin L and cathepsin S, and efficiently degr ade the invariant chain, unlike IFN-gamma -stimulated astrocytes that expre ss cathepsin L but not cathepsin S. The lack of cathepsin S proves to be dr amatic for the antigen-presentation capacity of astrocytes, which is nearly abolished when these cells are stimulated by a combination of IFN-gamma an d TNF-alpha. TNF-alpha indeed decreases cathepsin L activity as we show her e, leading to alterations in invariant chain processing, and hence in MHC c lass 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 comp onents in the regulation of the immune potential of astrocytes and microgli a, and provide evidence for a cell-specific regulation exerted by IFN-gamma and TNF-alpha on the expression and activity of cathepsins.