Destructive potential of the aspartyl protease cathepsin D in MHC class II-restricted antigen processing.
Whether specific proteases influence MHC class II antigen presentation is still not clearly defined. Cathepsin D, one of the most abundant lysosomal proteases, is thought to be dispensable for MHC class II antigen presentation, yet in vitro digestions of antigen substrates with endosomes/lysosomes from antigen-presenting cells sometimes reveal a dominant role for pepstatin-sensitive aspartyl proteases of which cathepsin D is the major representative. We tested whether the aspartyl protease substrate myoglobin requires cathepsin D activity for presentation to T cells. Surprisingly, in dendritic cells (DC) lacking cathepsin D, presentation of two different myoglobin T cell epitopes was enhanced rather than hindered. This paradox is resolved by the finding that pepstatin-sensitive myoglobin processing activity persists in lysosomes from cathepsin D-null DC and that this reduced activity, most likely due to cathepsin E, is closer to the optimum level required for myoglobin antigen presentation. Our results indicate redundancy among lysosomal aspartyl proteases and show that while processing activities can be productive for MHC class II T cell epitope generation at one level, they can become destructive above an optimal level.
Moss
Catherine X
CX
Division of Cell Biology & Immunology, Wellcome Trust Biocentre, University of Dundee, Dundee, UK.
Villadangos
Jose A
JA
Watts
Colin
C
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000201:enzymology / Q000276:immunology; D002402:Cathepsin D / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009211:Myoglobin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050661:Sperm Whale; D013379:Substrate Specificity / Q000235:genetics
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D009211:Myoglobin; D002402:Cathepsin D