title: Cysteine proteases in Langerhans cells limits presentation of cartilage derived type II collagen for autoreactive T cells.
abstract: Development of type-II collagen (CII)-induced arthritis (CIA) is dependent on activation of CII-reactive T cells. Dendritic cells (DCs) are believed to play a crucial role in antigen-specific priming of T cells but it is still unclear how the CII-reactive T cells are primed since Langerhans cells (LCs) are poor antigen-presenting cells for CII. In the present study we show that LCs, treated with cysteine protease inhibitors, are able to process and present CII to T-cell hybridomas specific for the immune-dominant glycosylated 259-270 peptide bound to the MHC class II molecule A(q). Interestingly, the self (mouse) CII peptide could also now be efficiently presented. The poor presentation by LCs is a peptide-specific effect, since both bovine CII (bCII) (presenting a different peptide on H-2(r)) and ovalbumin could be efficiently presented, and blockage of cysteine proteases did not enhance antigen presentation. The enhanced CII-presentation by cysteine protease inhibition is seen mainly in LCs and not in antigen-primed B cells or macrophages. B cell and macrophage presentation of CII occur even without protease inhibition and are only to a minor extent influenced by cysteine protease inhibition. These data suggest that a LC deficiency in processing of the immune-dominant CII epitope in both CIA and RA may limit the exposure of this self-antigen to T cells, but that presentation can be overcome by modulation of the peptide proteolysis during CII processing.
authors.affiliation: Department of Clinical Chemistry, Lund University, Sweden. Meirav.Holmdahl@inflam.lu.se
authors.forename: Meirav
authors.initials: M
authors.lastname: Holmdahl
authors.forename: Anders
authors.initials: A
authors.lastname: Grubb
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002356:Cartilage / Q000276:immunology; D024043:Collagen Type II / Q000276:immunology*; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology; D007801:Langerhans Cells / Q000201:enzymology* / Q000276:immunology*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D010436:Pepstatins / Q000494:pharmacology; D010455:Peptides / Q000276:immunology; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D024043:Collagen Type II; D010436:Pepstatins; D010455:Peptides; D010047:Ovalbumin; D003546:Cysteine Endopeptidases; D007930:Leucine; C024974:E 64; C031375:pepstatin