Pepstatin A-sensitive aspartic proteases in lysosome are involved in degradation of the invariant chain and antigen-processing in antigen presenting cells of mice infected with Leishmania major

We previously reported that CA074, a specific inhibitor of cathepsin B, sig nificantly deviated immune responses hom the disease-promoting Th2 type to the protective Th1 type in BALB/c mice infected with Leishmania major. Here in, we found that pepstatin A-sensitive aspartic proteases (PSAP) in lysoso mes seem to play a different role from that of cathepsin B in antigen-proce ssing and Ii-degradation. That is, cathepsin B appears to digest 16-, 28-, and 31-kDa peptides of soluble leishmania antigen (SLA), whereas PSAP seems to process mainly 28-kDa peptides. Furthermore, the latter protease contri buted to the degradation of Ii but cathepsin B did not. Following treatment with pepstatin A, both Th1 and Th2 responses were profoundly suppressed in resistant DBA/2 mice (H-2(d)) and in susceptible BALB/c mice (H-2d), and b oth strains of mice became markedly susceptible compared with the untreated groups, probably owing to failure in degradation of Ii and partly to failu re in digestion of 28-kDa peptide. (C) 2000 Academic Press.