Cathepsin S activity regulates antigen presentation and immunity
Cathepsin S activity regulates antigen presentation and immunity
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DOI：
10.1172/jci1158
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发表时间：
1998-06-01
影响因子：
15.9
通讯作者：
Chapman, HA
中科院分区：
文献类型：
--
作者：
Riese, RJ;Mitchell, RN;Chapman, HA
MHC II类分子在细胞表面展示抗原肽，以供CD 4（+）T细胞识别。在该过程中，蛋白水解是必需的，用于从II-Ii类复合物降解不变链（Ii）以允许随后的肽结合，以及用于产生抗原肽。半胱氨酸内切蛋白酶，组织蛋白酶S，介导人和小鼠抗原呈递细胞中的Ii降解。本文描述的研究检查了组织蛋白酶S抑制对抗原呈递和免疫的功能意义。在A20细胞中组织蛋白酶S的特异性抑制通过干扰II类肽结合而不是通过阻碍抗原的产生来显著损害卵清蛋白表位的呈递。向小鼠体内施用组织蛋白酶S抑制剂选择性地抑制脾细胞中组织蛋白酶S的活性，导致II类相关Ii分解产物的积累，减弱II类肽复合物的形成，并抑制抗原呈递。当用卵清蛋白而不是T细胞非依赖性抗原TNP-Ficoll免疫时，用抑制剂处理的小鼠具有减弱的抗体应答。在肺超敏反应的小鼠模型中，用抑制剂治疗也消除了IgE滴度的升高，并彻底阻断了肺中的嗜酸性粒细胞浸润。因此，在体内抑制组织蛋白酶S改变Ii加工、抗原呈递和免疫。这些数据确定选择性抑制半胱氨酸蛋白酶是哮喘和自身免疫性疾病过程的潜在治疗策略。
MHC class II molecules display antigenic peptides on cell surfaces for recognition by CD4(+) T cells. Proteolysis is required in this process both for degradation of invariant chain (Ii) from class II-Ii complexes to allow subsequent binding of peptides, and for generation of the antigenic peptides. The cysteine endoprotease, cathepsin S, mediates Ii degradation in human and mouse antigen-presenting cells. Studies described here examine the functional significance of cathepsin S inhibition on antigen presentation and immunity, Specific inhibition of cathepsin S in A20 cells markedly impaired presentation of an ovalbumin epitope by interfering with class II-peptide binding, not by obstructing generation of the antigen. Administration of a cathepsin S inhibitor to mice in vivo selectively inhibited activity of cathepsin S in splenocytes, resulting in accumulation of a class II-associated Ii breakdown product, attenuation of class II-peptide complex formation, and inhibition of antigen presentation. Mice treated with inhibitor had an attenuated antibody response when immunized with ovalbumin but not the T cell-independent antigen TNP-Ficoll. In a mouse model of pulmonary hypersensitivity, treatment with the inhibitor also abrogated a rise in IgE titers and profoundly blocked eosinophilic infiltration in the lung. Thus, inhibition of cathepsin S in vivo alters Ii processing, antigen presentation, and immunity. These data identify selective inhibition of cysteine proteases as a potential therapeutic strategy for asthma and autoimmune disease processes.