MHC class II molecules display antigenic peptides on cell surfaces for recognition by CD4(+) T cells. Proteolysis is required in this process both for degradation of invariant chain (Ii) from class II-Ii complexes to allow subsequent binding of peptides, and for generation of the antigenic peptides. The cysteine endoprotease, cathepsin S, mediates Ii degradation in human and mouse antigen-presenting cells. Studies described here examine the functional significance of cathepsin S inhibition on antigen presentation and immunity. Specific inhibition of cathepsin S in A20 cells markedly impaired presentation of an ovalbumin epitope by interfering with class II-peptide binding, not by obstructing generation of the antigen. Administration of a cathepsin S inhibitor to mice in vivo selectively inhibited activity of cathepsin S in splenocytes, resulting in accumulation of a class II-associated Ii breakdown product, attenuation of class II-peptide complex formation, and inhibition of antigen presentation. Mice treated with inhibitor had an attenuated antibody response when immunized with ovalbumin but not the T cell-independent antigen TNP-Ficoll. In a mouse model of pulmonary hypersensitivity, treatment with the inhibitor also abrogated a rise in IgE titers and profoundly blocked eosinophilic infiltration in the lung. Thus, inhibition of cathepsin S in vivo alters Ii processing, antigen presentation, and immunity. These data identify selective inhibition of cysteine proteases as a potential therapeutic strategy for asthma and autoimmune disease processes.
R J Riese, R N Mitchell, J A Villadangos, G P Shi, J T Palmer, E R Karp, G T De Sanctis, H L Ploegh, H A Chapman
Title and authors | Publication | Year |
---|---|---|
NOD and NOR mice exhibit comparable development of lacrimal gland secretory dysfunction but NOD mice have more severe autoimmune dacryoadenitis
Y Ju, SR Janga, W Klinngam, JA MacKay, D Hawley, D Zoukhri, MC Edman, SF Hamm-Alvarez |
Experimental Eye Research | 2018 |
Cysteine protease cathepsins in cardiovascular disease: from basic research to clinical trials
CL Liu, J Guo, X Zhang, GK Sukhova, P Libby, GP Shi |
Nature Reviews Cardiology | 2018 |
Cysteine cathepsins as a prospective target for anticancer therapies—current progress and prospects
A Pogorzelska, B Żołnowska, R Bartoszewski |
Biochimie | 2018 |
Class II MHC antigen processing in immune tolerance and inflammation
MM Jurewicz, LJ Stern |
Immunogenetics | 2018 |
Effects of Cross-Presentation, Antigen Processing, and Peptide Binding in HIV Evasion of T Cell Immunity
BF Frey, J Jiang, Y Sui, LF Boyd, B Yu, G Tatsuno, R Billeskov, S Solaymani-Mohammadi, PW Berman, DH Margulies, JA Berzofsky |
Journal of immunology (Baltimore, Md. : 1950) | 2018 |
Engineered hybrid spider silk particles as delivery system for peptide vaccines
M Lucke, I Mottas, T Herbst, C Hotz, L Römer, M Schierling, HM Herold, U Slotta, T Spinetti, T Scheibel, G Winter, C Bourquin, J Engert |
Biomaterials | 2018 |
Long-term dietary replacement of fishmeal and fish oil in diets for rainbow trout (Oncorhynchus mykiss): Effects on growth, whole body fatty acids and intestinal and hepatic gene expression
V Lazzarotto, F Médale, L Larroquet, G Corraze, S Martínez-Llorens |
PloS one | 2018 |
Immune effects of the neurotoxins ciguatoxins and brevetoxins
O Pierre, L Misery, M Talagas, RL Garrec |
Toxicon : official journal of the International Society on Toxinology | 2018 |
Proteomic analysis of lipopolysaccharide activated human monocytes
M Lausen, TB Poulsen, G Christiansen, K Kastaniegaard, A Stensballe, S Birkelund |
Molecular Immunology | 2018 |