Cytokines Regulate Proteolysis in Major Histocompatibility Complex Class II-dependent Antigen Presentation by Dendritic Cells

doi:10.1084/jem.193.8.881

Published online 9 April 2001.

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© The Rockefeller University Press, 0022-1007/2001/4/881/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 8, April 16, 2001 881-892

Original Article

Cytokines Regulate Proteolysis in Major Histocompatibility Complex Class II–dependent Antigen Presentation by Dendritic Cells

Edda Fiebiger^a,c, Paul Meraner^a, Ekkehard Weber^d, I-Fei Fang^a, Georg Stingl^a, Hidde Ploegh^c, and Dieter Maurer^a,b
^a Division of Immunology, Allergy, and Infectious Diseases, Department of Dermatology, University of Vienna Medical School,
^b Center of Molecular Medicine (CeMM) of the Austrian Academy of Sciences, A-1090 Vienna, Austria
^c Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
^d Department of Physiological Chemistry, Martin Luther University, 06097 Halle, Germany

Correspondence to: Dieter Maurer, Department of Dermatology/CeMM, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel:43-1-40400-7769 Fax:43-1-4031-900 E-mail:dieter.maurer{at}akh-wien.ac.at.

Endo/lysosomal proteases control two key events in antigen (Ag)presentation: the degradation of protein Ag and the generationof peptide-receptive major histocompatibility complex (MHC)class II molecules. Here we show that the proinflammatory cytokinestumor necrosis factor ${alpha}$ and interleukin (IL)-1ß rapidlyincrease the activity of cathepsin (cat) S and catB in humandendritic cells (DCs). As a consequence, a wave of MHC classII sodium dodecyl sulfate stable dimer formation ensues in acatS-dependent fashion. In contrast, the antiinflammatory cytokineIL-10 renders DCs incapable of upregulating catS and catB activityand in fact, attenuates the level of both enzymes. SuppressedcatS and catB activity delays MHC class II sodium dodecyl sulfatestable dimer formation and impairs Ag degradation. In DCs exposedto tetanus toxoid, IL-10 accordingly reduces the number of MHCclass II–peptide complexes accessible to tetanus toxoid–specificT cell receptors, as analyzed by measuring T cell receptor downregulationin Ag-specific T cell clones. Thus, the control of proteaseactivity by pro- and antiinflammatory cytokines is an essentialfeature of the Ag presentation properties of DCs.

Key Words: antigen-presenting cell, cathepsin, class II maturation, antigendegradation, TCR

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