Maekawa Y, Himeno K, Ishikawa H, Hisaeda H, Sakai T, Dainichi T, Asao T, Good R A, Katunuma N
Department of Parasitology and Immunology, University of Tokushima School of Medicine, Japan.
J Immunol. 1998 Sep 1;161(5):2120-7.
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-gamma 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.
激活后，CD4 +辅助性T细胞在功能上分化为两个亚群之一，即Th1或Th2。在Th分化之前，抗原必须被加工成肽表位，并与II类主要组织相容性复合体分子结合呈递给CD4 + T细胞。然而，负责这种抗原加工的蛋白酶尚未明确界定。当用组织蛋白酶B（一种消化外源性抗原蛋白的溶酶体半胱氨酸蛋白酶）的特异性抑制剂（CA074）处理易感染硕大利什曼原虫的BALB / c小鼠时，这些小鼠获得了对硕大利什曼原虫感染的抗性，并显示出免疫反应从Th2向Th1的转变；也就是说，与未处理和感染的小鼠产生IgG1和IgE并产生IL - 4相反，它们产生特异性IgG2a抗体并产生干扰素 - γ。CA074在体内和体外均干扰了溶酶体酶对硕大利什曼原虫抗原的消化。然而，这种抑制剂对硕大利什曼原虫的生长以及用抗CD3抗体刺激的T细胞功能没有任何直接影响。这些发现表明，组织蛋白酶B抑制剂可以将CD4 + T细胞分化从Th2转变为Th1，这表明抗原加工的改变调节了Th分化的极性。
