While interference with the class I MHC pathway by homologous to pathogen-encoded gene products, especially those of viruses, has been well documented, few examples type 2 cystatins were recently identified. Their sequence, homology to mammalian cystatins, and developmental of specific interference with the MHC class II pathway have been reported. Potential targets for expression pattern will be fully described elsewhere (W. F. Gregory et al., submitted). Bm-CPI-1 and Bm-CPI-2 such interference are the proteases that remove the invariant chain chaperone and generate (hereafter referred to as CPI-1 and CPI-2) both have the conserved Q-x-V-x-G and PW motifs that are found in all antigenic peptides. Indeed, recent studies indicate that immature dendritic cells express cystatin C to type 2 cystatins and are known to form part of the inhibitory site that is directed at the papain-like, or C1, family modulate cysteine protease activity and the expression of class II MHC molecules [1]. Here, we of cysteine proteases [2]. Interestingly, CPI-2 also has a conserved SND motif that was recently shown to consti- show that Bm-CPI-2, a recently discovered cystatin homolog produced by the filarial nematode parasite tute a distinct second inhibitory site that is specific for the C13 family of cysteine proteases, which includes Brugia malayi (W. F. Gregory et al., submitted), inhibits multiple cysteine protease activities found asparaginyl endopeptidase (AEP), or legumain [3]. In addition, Bm-CPI-2 is expressed and secreted during para- in the endosomes/lysosomes of human B lymphocyte lines. CPI-2 blocked the hydrolysis of sitic stages that mature in the mammalian host and, therefore, has the potential to interfere with host cysteine synthetic substrates favored by two different families of lysosomal cysteine proteases and protease activities. We therefore decided to focus on the CPI-2 protein. blocked the in vitro processing of the tetanus toxin antigen by purified lysosome fractions. Moreover, CPI-2 substantially inhibited the presentation of We first tested the capacity of CPI-2 to block protease selected T cell epitopes from tetanus toxin by living activities present in the endosomes and lysosomes of huantigen- presenting cells. Our studies provide the man antigen-presenting cells (APC). A preliminary analyfirst example of a product from a eukaryotic parasite sis showed that recombinant CPI-2 inhibited the cysteine that can directly interfere with antigen protease papain (W. F. Gregory et al.), raising the possibilpresentation, which, in turn, may suggest how filarial ity that lysosomal cysteine proteases might be targets of parasites might inactivate the host immune these parasite gene products. response to a helminth invader.