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*
Department of Parasitology and Immunology, University of Tokushima School of Medicine, Tokushima, Japan;
Chemistry Laboratory, Taiho Pharmaceutical Co., Hanno, Japan;
All Children’s Hospital, University of South Florida, St. Petersburg, FL; and
§
Institute for Health Sciences, Tokushima Bunri University, Tokushima, Japan
When activated, CD4+ T helper cells differentiate
functionally into one of two subsets, Th1 or Th2. Before the Th
differentiation, Ags must be processed into peptide epitopes and
presented to CD4+ T cells in association with MHC class II
molecules. However, the proteases responsible 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 protease that
digests exogenous antigenic proteins, those mice acquired resistance
against infection with L. major and showed the shift of
immune responses from Th2 to Th1; that is, they produced specific IgG2a
Ab and generated IFN-
in contrast to untreated and infected mice
that 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 in vitro. However, this inhibitor did not show any
direct influence on the growth of L. major and the
functions of T cells stimulated with anti-CD3 Ab. These findings
indicate that cathepsin B inhibitor could switch CD4+ T
cell differentiation from Th2 to Th1, suggesting that the alteration in
Ag processing modulates the polarity of Th
differentiation.
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