Fiebiger E, Meraner P, Weber E, Fang I F, Stingl G, Ploegh H, Maurer D
Division of Immunology, Allergy, and Infectious Diseases, Department of Dermatology, University of Vienna Medical School, Austria.
J Exp Med. 2001 Apr 16;193(8):881-92. doi: 10.1084/jem.193.8.881.
Endo/lysosomal proteases control two key events in antigen (Ag) presentation: the degradation of protein Ag and the generation of peptide-receptive major histocompatibility complex (MHC) class II molecules. Here we show that the proinflammatory cytokines tumor necrosis factor alpha and interleukin (IL)-1beta rapidly increase the activity of cathepsin (cat) S and catB in human dendritic cells (DCs). As a consequence, a wave of MHC class II sodium dodecyl sulfate stable dimer formation ensues in a catS-dependent fashion. In contrast, the antiinflammatory cytokine IL-10 renders DCs incapable of upregulating catS and catB activity and in fact, attenuates the level of both enzymes. Suppressed catS and catB activity delays MHC class II sodium dodecyl sulfate stable dimer formation and impairs Ag degradation. In DCs exposed to tetanus toxoid, IL-10 accordingly reduces the number of MHC class II-peptide complexes accessible to tetanus toxoid-specific T cell receptors, as analyzed by measuring T cell receptor downregulation in Ag-specific T cell clones. Thus, the control of protease activity by pro- and antiinflammatory cytokines is an essential feature of the Ag presentation properties of DCs.
内体/溶酶体蛋白酶控制抗原（Ag）呈递中的两个关键事件：蛋白质抗原的降解和肽受体主要组织相容性复合体（MHC）II类分子的生成。我们在此表明，促炎细胞因子肿瘤坏死因子α和白细胞介素（IL）-1β可迅速提高人树突状细胞（DC）中组织蛋白酶（cat）S和catB的活性。结果，以catS依赖的方式出现了一波MHC II类十二烷基硫酸钠稳定二聚体的形成。相反，抗炎细胞因子IL-10使DC无法上调catS和catB的活性，实际上还降低了这两种酶的水平。catS和catB活性的抑制会延迟MHC II类十二烷基硫酸钠稳定二聚体的形成，并损害抗原降解。在暴露于破伤风类毒素的DC中，通过测量抗原特异性T细胞克隆中的T细胞受体下调情况分析，IL-10相应地减少了破伤风类毒素特异性T细胞受体可及的MHC II类-肽复合物的数量。因此，促炎和抗炎细胞因子对蛋白酶活性的控制是DC抗原呈递特性的一个基本特征。
