Cytokines regulate proteolysis in major histocompatibility complex class II-dependent antigen presentation by dendritic cells

Endo/lysosomal proteases control two key events in antigen (Ag) presentatio n: the degradation of protein Ag and the generation of peptide-receptive ma jor histocompatibility complex (MHC) class II molecules. Here we show that the proinflammatory cytokines tumor necrosis factor alpha and interleukin ( IL)-1 beta rapidly increase the activity of cathepsin (cat) S and catB in h uman 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 bo th enzymes. Suppressed catS and catB activity delays MHC class II sodium do decyl sulfate stable dimer formation and impairs Ag degradation. In DCs exp osed to tetanus toxoid, IL-10 accordingly reduces the number of MHC class I I-peptide complexes accessible to tetanus toroid-specific T cell receptors, as analyzed by measuring T cell receptor downregulation in Ag-specific T c ell clones. Thus, the control of protease activity by pro- and antiinflamma tory cytokines is an essential feature of the Ag presentation properties of DCs.