Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia malayi, inhibits class II MHC-restricted antigen processing

While interference with the class I MHC pathway by pathogen-encoded gene pr oducts, especially those of viruses, has been well documented, few examples of specific interference with the MHC class II pathway have been reported, Potential targets for such interference are the proteases that remove the invariant chain chaperone and generate antigenic peptides, Indeed, recent s tudies indicate that immature dendritic cells express cystatin C to modulat e cysteine protease activity and the expression of class II MHC molecules [ 1], Here, we show that Bm-CPI-2, a recently discovered cystatin homolog pro duced by the filarial nematode parasite Brugia malayi (W, F. Gregory et al, , submitted), inhibits multiple cysteine protease activities found in the e ndosomes/lysosomes of human a lymphocyte lines. CPI-2 blocked the hydrolysi s of synthetic substrates favored by two different families of lysosomal cy steine proteases and blocked the in vitro processing of the tetanus toxin a ntigen by purified lysosome fractions. Moreover, CPI-2 substantially inhibi ted the presentation of selected T cell epitopes from tetanus toxin by livi ng antigen-presenting cells. Our studies provide the first example of a pro duct from a eukaryotic parasite that can directly interfere with antigen pr esentation, which, in turn, may suggest how filarial parasites might inacti vate the host immune response to a helminth invader.