SWITCH OF CD4(-CELL DIFFERENTIATION FROM TH2 TO TH1 BY TREATMENT WITHCATHEPSIN-B INHIBITOR IN EXPERIMENTAL LEISHMANIASIS() T)

When activated, CD4(+) T helper cells differentiate functionally into one of two subsets, Th1 or Th2, Before the Th differentiation, Ags mus t be processed into peptide epitopes and presented to CD4(+) T cells i n association with MHC class II molecules. However, the proteases resp onsible for this Ag processing have not been well defined. When BALB/c mice susceptible to infection with Leishmania major were treated with a specific inhibitor (CA074) of cathepsin B, a lysosomal cysteine pro tease that digests exogenous antigenic proteins, those mice acquired r esistance against infection with L. major and showed the shift of immu ne responses from Th2 to Th1; that is, they produced specific IgG2a Ab and generated IFN-gamma in contrast to untreated and infected mice th at produced IgG1 and IgE and generated IL-4. CA074 interfered with the digestion of L, major Ags with lysosomal enzymes in vivo as well as i n vitro. However, this inhibitor did not show any direct influence on the growth of L, major and the functions of T cells stimulated with an ti-CD3 Ab. These findings indicate that cathepsin B inhibitor could sw itch CD4(+) T cell differentiation from Th2 to Th1, suggesting that th e alteration in Ag processing modulates the polarity of Th differentia tion.